Comparison of new secondgeneration H1 receptor blockers with some molecules; a study involving DFT, molecular docking, ADMET, biological target and activity

Abstract

Although the antiallergic properties of compounds such as CAPE, Melatonin, Curcumin, and Vitamin C have been poorly discussed by experimental studies, the antiallergic properties of these famous molecules have never been discussed with calculations. The histamine-1 receptor (H1R) belongs to the family of rhodopsin-like G-protein-coupled receptors expressed in cells that mediate allergies and other pathophysiological diseases. In this study, pharmacological activities of FDA-approved second generation H1 antihistamines (Levocetirizine, desloratadine and fexofenadine) and molecules such as CAPE, Melatonin, Curcumin, Vitamin C, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) profiles, density functional theory (DFT), molecular docking, biological targets and activities were compared by calculating. Since drug development is an extremely risky, costly and time-consuming process, the data obtained in this study will facilitate and guide future studies. It will also enable researchers to focus on the most promising compounds, providing an effective design strategy. Their pharmacological activity was carried out using computer-based computational techniques including DFT, molecular docking, ADMET analysis, biological targeting, and activity methods. The best binding sites of Desloratadine, Levocetirizine, Fexofenadine, CAPE, Quercetin, Melatonin, curcumin, Vitamin C ligands to Desmoglein 1, Human Histamine H1 receptor, IgE and IL13 protons were determined by molecular docking method and binding energy and interaction states were analyzed. Fexofenadine and Quercetin ligand showed the most effective binding affinity. Melatonin had the best Caco-2 permeability PPB values of Quercetin, CAPE and Curcumin were at optimal levels. On the OATP1B1 and OATP1B3 of curcumin and CAPE, Quercetin was found to have strong inhibition effects on BCRP. Melatonin and CAPE were found to have the highest inhibition values on CYP1A2, while CAPE had the highest inhibition values on CYP2C19 and CYP2C9. Vitamin C and Quercetin were found to be safer in terms of cardiac toxicity and mutagenic risks, while Desloratadine and Levocetirizine carried high risks of neurotoxicity and hematotoxicity, while CAPE was noted for its high enzyme inhibitory activities and low toxicity profiles, while the hERG blockade, DILI, and cytotoxicity values of other compounds pointed to various safety concerns. This study demonstrated the potential of machine learning methods in understanding and discovering H1 receptor blockers. The results obtained provide important clues in the development of important strategies in the clinical use of H1 receptor blockers. In the light of these data, CAPE and Quercetin are remarkable molecules.

Introduction

The incidence of allergic reactions, which occur because of the immune system’s hypersensitivity to normally harmless substances in the environment, increases every year. These allergic reactions occur in a variety of forms, including atopic dermatitis, allergic rhinitis, food allergies and asthma [1]. The increase in allergic disorders is associated with ‘Western lifestyles’, especially in developing and industrialized countries. Similarly, autoimmune diseases and other chronic inflammatory disorders are becoming more common in parallel with urbanization and industrialization [2]. Many drugs have been developed to treat allergic disorders, such as immunosuppressants, antihistamines, and steroids [3,4,5]. Antihistamines, especially H1 antihistamines, are commonly used in the treatment of allergic rhinitis, urticaria and other allergic diseases, often to reverse elevated histamine [6]. Histamine is an important biogenic amine in the human body, synthesized from l-histidine by the enzyme histidine decarboxylase. Histamine, a critical mediator of IgE/mast cell-mediated anaphylaxis that acts as a neurotransmitter and regulator of gastric acid secretion, exerts its biological effects through four different histamine receptor subtypes (H1R, H2R, H3R, and H4R) from the superfamily of G-protein-coupled receptors. Histamine plays an important role in a variety of physiological and pathophysiological conditions by activating these receptors, which are commonly found in central nervous system neurons, B cells in the gastric mucosa, mast cells, basophils, and various other cells [7,8,9,10,11]. Histamine is a neurotransmitter, a critical mediator of IgE/mast cell-mediated anaphylaxis, and a regulator of gastric acid secretion. Antihistamines with reverse agonism to the histamine receptor usually show activity at the H1, H2 and H3 receptors [12]. IgE antibodies and mast cells are highly linked to the pathophysiology of anaphylaxis and other acute allergic reactions [13]. IL-13, which partially regulates IgE production, has been shown to significantly reduce the expression of essential structural proteins such as desmoglein 1 and lipid composition, which is important for normal skin barrier function, thanks to STAT6 activation, which has a major effect on epidermal barrier function and local immune response [14, 15]. Since the successful development of the first antihistamine in 1937, the antihistamine has evolved into improved varieties in the form of first-generation, second-generation and third-generation antihistamines [6, 16]. Histamine H1 receptors are involved in a variety of functions, including vascular dilation, vascular permeability, blood pressure regulation, sleep, and memory. These receptors are found on the surfaces of vascular endothelial cells, smooth muscle cells, neurons and immune cells in the skin and mucous membranes [17]. Furthermore, H1R activation mediates many of the symptoms of type I allergic reactions, including pruritus, erythema, and edema [18]. Levocetirizine, loratadine, desloratadine and fexofenadine are H1R antagonists and therefore inhibit the H1 receptor and the effects of its activation [19]. New second-generation H1 antihistamines such as levocetirizine, fexofenadine and desloratadine, derived from the active metabolites or optical isomers of second-generation antihistamines, are used in the treatment of seasonal and continuous allergic rhinitis and urticaria [20, 21]. Although antihistamines are generally safe, they cause adverse reactions such as cardiotoxicity, central inhibition, and anticholinergic effects in some patients [6]. First-generation H1 antihistamines can have a variety of adverse effects on many body systems. However, the greatest concern is the tendency of these drugs to interfere with H1 receptors in the central nervous system, even at recommended doses. This can lead to central nervous system symptoms such as drowsiness, sedation, sleepiness, fatigue, and headache, and can have adverse effects on cognitive function, memory, and psychomotor skills [22]. Deaths attributed to first-generation H1 antihistamines have been reported in the literature for more than 60 years due to accidental overdose, suicide, and (infants) homicide [23]. Large (e.g., up to 20- to 30-fold) overdoses of second-generation H1 antihistamines such as fexofenadine, loratadine and cetirizine have not been causally associated with cardiovascular adverse events or serious CNS or deaths [22,23,24]. In real-world prescription event monitoring studies conducted in thousands of people with allergic rhinitis within the first 30 days of the introduction of a new H1 antihistamine in the UK, a low risk of sedation was reported for cetirizine, desloratadine, fexofenadine, levocetirizine and loratadine [25]. Drug discovery, in the process of identifying and developing new drugs, has traditionally relied on time-consuming and labor-intensive techniques such as trial-and-error methods and high-throughput screening. However, machine learning has the potential to speed up and improve this process, with its ability to analyze large datasets more effectively and precisely [26]. Increasing evidence confirms this notion. [27, 28]. Absorption, Distribution, Metabolism, Excretion, Toxicity (ADMET) are critical parameters for the discovery and optimization of new drugs. This has been known for a long time, and pharmaceutical companies are investing heavily in developing new assays and increasing their testing capacity, enabling them to characterize thousands of compounds in high-quality in vitro ADMET assays. Data, algorithms, and identifiers all contribute to model quality [29]. Understanding how drugs and substances interact with macromolecular receptors in the human body and the mechanisms of these interactions plays a vital role in the design and development of biologically active compounds. Molecular docking is widely used as a method in drug design based on the specific three-dimensional structure of the macromolecular receptor and its effective interactions with ligands at the active site within this structure. This method allows the selection of molecules with better spatial and electronic coherence and higher affinity energy [30]. Docking applications include methods such as virtual screening, identification of active sites of receptors, drug design, estimation of free binding energy, understanding the mechanisms of function of enzymes, and protein engineering [31]. Curcumin is one of the most important natural compounds with high potential in modulating immune responses and therapeutic potential. Research has shown that curcumin, due to its low cost, low toxicity, broad pharmacological activities, and effect on multiple targets, has a therapeutic potential in the treatment or management of many diseases, including immune-mediated inflammatory disorders. Since the correct functioning and balance of immune responses are critical in allergic diseases, curcumin, a natural immunomodulator, has a positive effect on allergic reactions by regulating and controlling impaired immune responses. [32]. Caffeic acid phenethyl ester (CAPE) is one of the main active ingredients of propolis, a natural product, and has unique biological properties such as anti-tumor, anti-fungal, anti-oxidation, anti-bacterial, anti-viral, anti-inflammatory and immune regulating. It is thought that CAPE exerts an antiallergic effect and this may be a result of its protective effect against IgE-mediated allergy [33, 34]. Melatonin is a hormone that regulates the sleep cycle, has a powerful antioxidant, cytoprotective, immunomodulator, anti-apoptotic and anti-inflammatory effect, and is mostly produced by the pineal gland from the amino acid tryptophan. In addition, Melatonin is effective in hypopigmentation processes and in the prevention of skin aging. It is recommended to be used in the treatment of skin diseases such as atopic dermatitis, chronic spontaneous urticaria and for photoprotection [35, 36]. Quercetin is a natural flavonoid known for its antioxidant properties and anti-allergic effects, and it can be considered an effective supplement in the management of diseases such as asthma, allergic rhinitis, and atopic dermatitis. Quercetin has the potential to reduce eosinophil and neutrophil uptake, activation of bronchial epithelial cells, collagen and mucus production, and airway hyperactivity. Thanks to these properties, quercetin is thought to play an important role in the treatment of allergic diseases [37]. Vitamin C, which is used in modern medical supplements, treats a variety of disorders associated with inflammation, oxidative stress, and immune dysregulation [38]. Vitamin C administration has been shown to improve symptoms of allergic rhinitis such as sneezing, lacrimation, itching, and weakness [39]. Vitamin C is a water-soluble antioxidant with immune-regulating effects. Allergy sufferers tend to produce various types of reactive oxygen species from the cells lining the airways, resulting in a weakened antioxidant defense mechanism and pathological inflammatory changes in the nasal mucosa. These changes include lipid peroxidation, increased sensitivity and reactivity of the mucosa, production of chemotactic molecules, and increased vascular permeability [40]. In one study, high doses of intravenous vitamin C were reported to show positive clinical benefits in patients with both acute and chronic allergic rhinitis [41]. To the best of our knowledge, prospective, long-term, randomized, controlled studies on the safety and pharmacological properties of new second-generation H1 antihistamines have not been adequately published so far. Although there are hundreds of studies on molecules such as CAPE, Melatonin, Curcumin, Vitamin C, there are no studies with pharmacological, biometric and cheminformatics data in the literature, and the antiallergic properties of these compounds are weak in experimental studies. In addition, there are almost no studies discussing the efficacy and side effects of all of them. The main purpose of this study is to reduce the number of in vitro or in vivo ADMET, biological target experiments, to enable researchers to better focus their experiments on the most promising compounds, to evaluate the second generation of H1 antihistamines (H1R blockers) desloratadine, levocetirizine and fexofenadine and candidate molecules by in silico analysis. In addition, it is to design and analyze new potential antihistamine candidates that show superior biological activity compared to existing antihistamines. The aim of this is to make inferences about the transportability of these new candidate molecules to the preclinical stage and their clinical potential. We hope to achieve this goal through molecular docking computational studies of ligands such as Desloratadine, Levocetirizine, Fexofenadine, CAPE, Quercetin, Melatonin, Curcumin, Vitamin C and structures known to be targets in allergic diseases such as Desmoglein 1 (AlphaFold ID: AF-102413-F1), Human H1 receptor (PDB ID: 3RZE), IgE (PDB ID: 3H9Y) and IL13 (PDB ID: 1IJZ). Further support these analyses, DFT calculations were employed to elucidate the electronic and structural properties of the studied molecules, offering valuable insights into their reactivity, stability, and potential interaction mechanisms with biological targets. Considering the potential of this work can contribute to further research in this direction by guiding these units of study, ultimately benefiting humanity [42, 43].

Materials and methods

Physicochemical, Molecular Descriptor Analysis and ADMET

Swiss-ADME (http://www.swissadme.ch/): is a free web tool offered by the Swiss Institute of Bioinformatics, Physicochemical properties, lipophilicity, drug similarity and bioavailability radar that provides the pharmacokinetic profile of drugs or compounds were examined [43,44,45]. Desloratadine, Levocetirizine, Fexofenadine, CAPE, Quercetin, Melatonin, Curcumin, Vitamin C have been subjected to in silico calculations of Absorption, Distribution, Metabolism, Excretion, Toxicity properties in ADMETlab 3.0 software (https://admetlab3.scbdd.com) [46].

Identification of biological targets by molecules

Potential biological targets of Desloratadine, Levocetirizine, Fexofenadine, CAPE, Quercetin, Melatonin, Curcumin, Vitamin C were estimated using the web tool MolPredictX, https://www.molpredictx.ufpb.br/. Potential targets, outcome, probability of activity or inactivity, and reliability are reported in the same table. K: Predicted Outcome, L: Probability, M: Probability Active, N: Probability Inactive. If the result is Active and probability = 1.0, then the result is marked (**); If the result is Active and probability = 0.6 to 0.8, the result is marked (*). If the result is Inactive and probability = 06–1.0, no signal was given [47].

Biological activity site of metabolism

Biological activity determination of the site of metabolism were determined using a prediction service, Prediction of Activity Spectra for Substances (PASS) Online (Way2Drug, https://www.way2drug.com/passonline/). Based on the leave-oneout-cross validation estimate, the average amount of prediction is about 95%. The mentioned web site contains many online bioinformatics tools which can be accessed through the link given above or by name. This website requires website user registration which includes many online bioinformatics tools that can be accessed from the link or name given above. Once these are accomplished, many medical properties can be analyzed using molecular structure information [48, 49]

Molecular modeling studies

Ligand system

The chemical structures of Desloratadine, Levocetirizine, Fexofenadine, CAPE, Quercetin, Melatonin, Curcumin and Vitamin C were obtained from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/). Details about Compound Identifier and structures of molecules used as ligands are given in Table 1.

Table 1 Compound identifier and structures of molecules used as ligands

Protein system

Desmoglein 1 (PDB ID: AF-102413-F1) protein structure retrieved from alphafold database (https://alphafold.ebi.ac.uk/entry/Q02413). Human H1 receptor (PDB ID: 3RZE), IgE (PDB ID: 3H9Y) and IL13 (PDB ID: 1IJZ) protein structures were obtained from the protein database (https://www.rcsb.org/). The information of the proteins is given in Table 2.

Table 2 3D structures of Target proteins

Molecular docking method

Molecular docking studies were performed based on the procedure published by Oner [50,51,52].In this process, UCSF Chimera, AutoDock Vina, Avogadro software, Biovia Discovery Studio Visualizer and PyMOL visualisation software were used. The binding pocket coordinates of Desmoglein 1 with Human Histamine H1 Receptor, IgE and IL3 proteins are centre x,y,z: − 2.32 Å, 14.99 Å, − 10.60 Å/Size x,y,z: 80.00, 80.00, 80.00, centre x,y,z: 27.44, 36.36, 36.38/size x,y,z: 80, 80, 80, centre x,y,z: 11.83, 40.18, 50.75/size x,y,z: 80, 80, 80 and centre x,y,z: 0.39, 0.06, − 0.279/dimension x,y,z: 80, 80, 80 [53,54,55,56,57].

DFT

Geometry optimization approaches were performed utilizing the Gaussian 09 software package, employing quantum chemical calculations based on DFT (B3LYP with a 6–311++ G(d,p). The calculations included the determination of the ΔE between the highest occupied HOMO and LUMO. Additionally, parameters such as softness (s), electrophilicity (ω), nucleophilicity (Nu), hardness (η) and electronegativity (χ) were evaluated. The dipole moment (μ) and Mulliken charges on the backbone atoms were also calculated using these quantum chemistry methods [58,59,60,61,62,63,64,65,66,67].

$$\Delta E = E_{LUMO} - E_{HOMO}$$

(1)

$$A = - E_{LUMO}$$

(2)

$$I = - E_{HOMO}$$

(3)

$$\upeta = \frac{1}{2}\left( {I - A} \right)$$

(4)

$$s = 1/\upeta$$

(5)

$$\chi = 1/2\left( {I + A} \right)$$

(6)

$$\omega = \frac{{\chi_{{}}^{2} }}{{2\upeta }}$$

(7)

$$Nu = 1/\omega$$

(8)

These calculations provide a comprehensive understanding of the electronic properties of the molecules under study, which is essential for predicting their chemical reactivity and stability. By elucidating these properties, the data can offer critical insights into the molecular behavior and potential applications, both chemically and biologically. In chemical applications, this understanding aids in the design and synthesis of new compounds with desired reactivity and stability profiles. Biologically, information is important for predicting the interaction of these molecules with biological targets, optimizing their efficacy as pharmaceuticals, and assessing their safety and metabolic stability.

Results and discussion

Identifying interactions between drugs and their targets is critical for the development of new drugs. In vitro screening experiments, i.e. biological analyses, are often used to identify these interactions. The preclinical stage lays the critical foundations and faces a significant churn rate of about 93% as a challenging stage in drug development. Therefore, there is a need to reduce research and development costs to increase the probability of success and increase process efficiency in the drug development phase. This means that machine learning is becoming increasingly important in areas such as cheminformatics and bioinformatics instead of traditional drug development methods. AI-powered methods provide fast and accurate predictions of biological and chemical properties, accelerating the replacement of traditional methods with more effective and accurate methodologies [68,69,70,71]. In the drug discovery process, ADMET properties play an important role in determining efficacy and safety. In clinical trials, ADMET's computational analyses allow focusing on the most promising components and provide an effective design strategy. [29, 67, 72]. Clinical failures of approximately 50% of purposeful new drug admissions are attributed to inadequate ADMET qualifications [46]. DFT is useful in identifying inhibitory effects on pharmacological properties and drug targets [73]. Molecular docking, on the other hand, is one of the most popular and successful structure-based silico methods that helps predict the affinity of ligands to bind to receptor proteins or the interactions that occur between molecules and biological targets. [74, 75]. In molecular docking studies, two molecules that are expected to form a stable complex when bound together are used and these molecules are generally called ligand and receptor. Molecular docking also covers pair possibilities such as protein-DNA, protein-RNA, protein–sugar, protein-peptide and protein-small compounds. In pharmaceutical discovery, usually the ligand is a small molecule and the receptor is a biological macromolecule such as a protein or DNA [76, 77]. H-bonds are important in the structural integrity of many biological molecules, including proteins and DNA, and are important in drug-receptor interactions [78]. Conventional hydrogen bonds (NH–O, OH–O, OH–O, OH–N and NH–N) represent the main stabilizing forces in biomolecular structure [79]. Interaction types such as pi-alkyl bonding help to increase the hydrophobic interaction of the ligand in the binding pocket of the receptor [80]. Van der Waals forces are decisive in protein–ligand complex formation and it has been shown by various studies that these interactions are very important in the binding affinity of the ligand to the protein [81, 82].

H1R, which is widely distributed in the body in epithelial cells and smooth vascular, neuronal, glial and immune cells, can cause allergic and inflammatory symptoms when activated by histamine secreted by Mast cells or basophils. For this reason, it has been extensively targeted in the development of antihistamines. [8, 10, 83, 84]. Second-generation antihistamines, thanks to their high H1R selectivity, usually do not cross the blood–brain barrier and bind predominantly to peripheral H1R, so CNS side effects are minimal or non-existent. However, despite their advantages, such as minimal blood–brain barrier penetration, efforts are underway to develop next-generation antihistamines that offer higher efficacy and safety. [6, 8, 10, 85, 86]. CAPE, Quercetin, Curcumin and Vitamin C are anti-allergic compounds. [32, 36, 37, 87]. In addition to its important immunomodulatory properties, melatonin is used to correct sleep disorders in people with atopic dermatitis and chronic spontaneous urticaria accompanying intense itching [35]. In this study, we are looking for answers to these questions as to whether compounds such as CAPE, Quercetin, Curcumin and Vitamin C have antiallergic/antihistamine properties and whether there is hope for allergic diseases. Again, in this study, we present the comparison of the pharmacological activities, ADMET profiles, DFT, biological targets and activities of the second FDA-approved new generation H1 antihistamines Levocetirizine, desloratadine and fexofenadine with CAPE, Quercetin, Curcumin and Vitamin C. Finally, molecular docking studies were performed with IgE, H1R, IL13 and Desmoglein-1, which are the most important proteins associated with allergy. These calculations and comparisons contain original data due to the fact that they are the first. Rapid assessment of the drug similarity of Desloratadine, Levocetirizine, Fexofenadine, CAPE, Quercetin, Melatonin, Curcumin, Vitamin C to the drug was carried out through graphical representation of bioavailability. A radar map was created to evaluate and compare these compounds using six physicochemical properties such as size, polarity, lipophilicity, solubility, flexibility, and saturation. The pink area shown in the diagram represents the optimal range of values for each parameter.

Lipophilicity, most commonly referred to as LogP, represents the concentration ratio of a compound between two phases, oil and liquid phases. Lipophilicity, one of the key properties of a potential drug that determines its solubility, ability to cross cell barriers, and its ability to move to a molecular target, affects pharmacokinetic processes such as ADMET [88, 89]. Drug particle size is one of the significant challenges as the particles need to move from the external environment to the circulation or interstitial fluid and through cell membranes for cellular internalization. Small particles are probably easier to internalize, but are subject to rapid cleaning. Large-sized particles don’t cross biological barriers as easily, but their size distribution is easier to control. This percentage size should be brought to the desired range due to the application routes [90]. Water Solubility, All estimated values are defined as the decimal logarithm of the molar solubility in water (log S). Having a soluble molecule largely includes many drug improvement activities, primarily ease of use and formation. In addition, for the formation processes of oral administration, the components are an important feature to combine absorption [91, 92].

Desloratadine, Levocetirizine, Melatonin and Vitamin C have values that fall within this optimal range in terms of all criteria. However, according to these diagrams, Fexofenadine exhibited an optimal range for all criteria except Flexibility, CAPE, Quercetin, Curcumin (Fig. 1). Desloratadine, Levocetirizine, Fexofenadine, CAPE, Quercetin, Melatonin, Curcumin, Vitamin C Rotatable bonds values were 0, 8, 10, 6, 1,5, 8, 2 and H-bond acceptors values were 2,5,5,4,7,2,6,6, respectively. Desloratadine, Levocetirizine, Fexofenadine, CAPE, Quercetin, Melatonin, Curcumin, Vitamin C Fraction Csp3 values were 0.32, 0.38, 0.41, 0.12, 0.00, 0.31, 0.14, 0.50, respectively. CAPE, Quercetin, Curcumin were below 0.25. Desloratadine, Levocetirizine, Fexofenadine, CAPE, Quercetin, Melatonin, Curcumin, Vitamin C MW value respectively; 310.82, 388.89, 501.6, 284.3, 302.2, 232.28, 368.38, 176.12. This value should be in the range of 180 to 480. The compound that does not fit into this range is Fexofenadine. It was the Quercetin molecule whose value did not fit into this range. Expected TPSA values between 20 Ų and 130 Ų are respectively; 24.92, 53.01, 81.00, 66.76, 131.36, 54.12, 93.06, 107.22. It was the Quercetin molecule whose value did not fit into this range. Estimates are based on drug similarity rules. Desloratadine, Levocetirizine, CAPE, Quercetin, Melatonin, Curcumin completely passed the Lipinski, Ghose, Veber, Egan, Muegge rules, Fexofenadine did not pass the Lipinski (1 violation) and Ghose rules (3 violations), while Vitamin C did not pass the Ghose (2 violations) and Muegge rules (1 violation). All compounds exhibited 55% oral bioavailability, reflecting as an oral drug. Desloratadine, Levocetirizine, Fexofenadine, CAPE, Quercetin, Melatonin, Curcumin, and Vitamin C have Log Po/w values below 5, which is an indication of good permeability and absorption through the cell membrane. However, the solubility of a molecule is a critical factor that significantly affects the absorption of the compound throughout the formulation process (Table 3). A comprehensive evaluation of these findings indicates that Desloratadine, Levocetirizine, Melatonin and Vitamin C exhibit good results. While the properties of fexofenadine and curcumin, such as size, flexibility, etc., do not comply with some criteria, Quercetin and CAPE do not meet some optimal ranges, especially polarity and saturation values [44]. The Synthetic Accessibility Score is used to assess how simple it is to synthesize a medicinal molecule. The SA score is calculated by adding up the contributions made by the parts of each molecule and then dividing that sum by the number of parts in the molecule. This grading is beneficial for drug discovery as it evaluates the ease of synthesis of a molecule by assisting in several steps in the drug development process [93, 94]. It was created to evaluate a large number of potential drug-like candidates generated by software models, combinatorial libraries, or de novo molecular design methods to evaluate SA or facilitate its synthesis [95].

Fig. 1

Radar map of Desloratadine (A), Levocetirizine (B), Fexofenadine (C), CAPE (D), Quercetin (E), Melatonin (F), Curcumin (G), Vitamin C (H) molecule from Swissadme database. The pink area shows the optimal range for each property (Lipophilicity: XLOGP3 between − 0.7 and + 5.0, Size: MW between 150 and 500 g/mol, polarity: TPSA between 20 and 130 Å2, solubility: log S not higher than 6, Saturation: fraction of carbons in the sp3 hybridization not less than 0.25, and Flexibility: no more than 9 rotatable bonds [44]

Table 3 Physicochemical properties of molecules

Absorption properties of desloratadine, levocetirizine, fexofenadine, CAPE, quercetin, melatonin, curcumin and Vitamin C

To evaluate the absorption property of Desloratadine, Levocetirizine, Fexofenadine, CAPE, Quercetin, Melatonin, Curcumin, Vitamin C, Caco-2-Permeability, MDCK Permeability, PAMPA, substrate or inhibitor (P-gpinh/P-gpsub), Human intestinal absorption (HIA) was estimated. In addition, 20% bioavailability (F20), 30% bioavailability (F30), 50% bioavailability (F50) were presented. Various in vivo, ex vivo, and in vitro analysis systems have been developed to predict small intestinal absorption [96]. The Caco-2 cell line is commonly used as an in vitro gut model system to assess the intestinal permeability of novel chemical entities. Importantly, Caco-2 cells exhibit many of the morphological and functional characteristics of human intestinal epithelial cells [97]. One of the most popular cellular in vitro membrane permeability methods used in drug discovery is Madin-Darby Canine Kidney (MDCK) monolayer assays [98]. Caco-2 permeability was Desloratadine (− 4.889), Levocetirizine (− 5.597), Fexofenadine (− 5.098), CAPE (− 5.216), Quercetin (− 6.177), Melatonin (− 4.835), Curcumin (− 5.417), Vitamin C (− 5.883). Melatonin had the best Caco-2 permeability value, followed by Desloratadine, but Quercetin had the lowest permeability. The increase of high negative Caco-2 mainly means that it has the potential to ensure their permeability. This means that its absorption from the intestine is better than other compounds (Table 4). When PAMPA values were examined, they were Desloratadine (0.072), Levocetirizine (0.853), Fexofenadine (0.953), CAPE (0.169), Quercetin (0.581), Melatonin (0.33), Curcumin (0.124), Vitamin C (0.908). The molecule with the most favorable PAMPA value was Desloratatanine (Table 4) Applied at the early stage of drug discovery for the prediction of passive diffusion of compounds across phospholipid membranes, PAMPA is a cost-effective and robust method with good reproducibility. Since they have high PAMPA values, they can effectively pass through lipid membranes through passive diffusion. This indicates that the passage of these compounds through cell membranes and therefore through the intestinal epithelium may also be high [99]. Levocetirizine also exhibits high bioavailability and absorption, which is consistent with its clinical efficacy despite the lack of specific PAMPA value. Multidrug resistance and its effect on the pharmacokinetics of clinically important drugs are widely accepted that P-glycoprotein (P-gp) is an important in the active transport of various substrates with different structures from cells [100, 101]. When Pgp-inhibitor and Pgp-Substrate values were examined, important findings were found in the Curcumin molecule. Curcumin was found to be Pgp-inhibitor (0.022) and Pgp-Substrate (0.004). Human intestinal absorption (HIA), which is a major obstacle in the formulation of new drug substances, is one of the most important features of ADME. Desloratadine (0.0), Levocetirizine (0.0), Fexofenadine (0.0), Curcumin (0.05) HIA values were remarkable [102] (Table 4). Understanding the bioavailability of these compounds is important for their clinical efficacy, dosing strategies, and potential side effects. When F20%, F30%, F50% values were examined, Desloratadine (0.0; 0.005; 0.023), Levocetirizine (0.0; 0.0; 0.0), Fexofenadine (0.988; 0.99; 0.999), CAPE (0.915; 0.952; 0.982), Quercetin (0.504; 0.991; 0.999), Melatonin (0.255; 0.063; 0.705), Curcumin (0.485; 0.465; 1.0), Vitamin C (0.328; 0.709; 0.694). When assessing these bioavailability probability values, the pharmacokinetic properties of each compound and its possible effects on its clinical efficacy are considered. The probability values of levocetirizine are zero, which means that there is a high probability that the bioavailability of the drug is above 50%. This suggests that the efficacy of levocetirizine is very high and has an advantage in clinical use, since it can exert the desired effect even at low doses. The bioavailability of CAPE also appears to be low. Despite its important functions, this compound may not be able to exert its desired therapeutic effects because it is not sufficiently absorbed in the body. Curcumin has low bioavailability, especially with a 100% probability of the F50% level. This means that the bioavailability issues of Curcumin are very serious. When we look at the values of Vitamin C and Melatonin at a moderate level, it can be interpreted that it may not show full effectiveness in the intake of both (Table 4).

Table 4 Absorbsion properties of molecules

Distribution properties of desloratadine, levocetirizine, fexofenadine, CAPE, quercetin, melatonin, curcumin and Vitamin C

Although PPB predicts that the effectiveness of a drug is affected by how it binds to proteins in the blood plasma, it is believed to have a significant effect on the rate of drug diffusion (flow in and out flow) between plasma and tissues, and hence this affects the volume of distribution (Vdss) of drugs. The less the drug binds, the more effectively it can cross or spread across cell membranes [103,104,105]. When PPB values were examined, they were Quercetin (98.66), CAPE (93.609), Curcumin (90.858), Levocetirizine (83.597), Desloratadine (81.8), Fexofenadine (70.499), Melatonin (51.164), Vit C (34.428). PPB is important for understanding the various characteristics of drug candidates, including drug-drug interaction, antimicrobial activity, drug clearance, volume of distribution, and therapeutic index. Quercetin, CAPE and Curcumin had optimal value (Optimal: < 90%). (Table 5). OATP1B1 inhibitory values were Curcumin (0.996), CAPE (0.973), Quercetin (0.94), Desloratadine (0.832), Vitamin C (0.789), Melatonin (0.493), Levocetirizine (0.001), Fexofenadine (0.0). OATP1B3 inhibitory values were Curcumin (1.0), CAPE (0.919), Quercetin (0.999), Desloratadine (0.604), Vitamin C (0.98), Melatonin (0.366), Levocetirizine (0.002), Fexofenadine (0.0) (Table 5). Organic anion transporter polypeptides (OATPs) 1B1 and OATP1B3 have been identified and characterized in the sinusoidal membrane of hepatic tissue and are membrane proteins that provide hepatic uptake of a large number of therapeutic drugs and endogenous compounds, as well as excretion of bile; this is an important step in the elimination of drugs from the human body. Many of the inhibitors with trans-inhibitory effects on OATP1B1/3 have also been reported to cause time-dependent inhibition of OATP1B1/3 [106,107,108]. The fact that they have a very strong inhibition effect on Curcumin, CAPE, Quercetin OATP1B1 suggests that by suppressing OATP1B1 these compounds, they can increase plasma levels of carrier-borne drugs and potentially cause interactions. However, when Levocetirizine and Fexofenadine values are examined, it shows that there are almost no inhibition effects on OATP1B1, this does not affect the OATP1B1 carrier and the risk of interaction with other drugs is low (Table 5). MRP1 can transport conjugated organic anions produced by the Phase I and Phase II metabolism of endo- and xenobiotics [109]. Most of these organic anion substrates are glutathione, glucuronate, or sulfate conjugated molecules [97]. In the strategy of inhibiting MRP1, the ability of this protein to bind or expel substrates is inhibited, usually by using small molecules. This increases the effectiveness of the drugs by increasing the accumulation of chemotherapeutic drugs in the cell [110, 111]. When MRP1 inhibitor values were examined, they were Fexofenadine (1), Desloratadine (0.980), Levocetirizine (0.996), Quercetin (0.838), Curcumin (0.881), Vitamin C (0.729), Melatonin (0.352), CAPE (0.31%). (Table 5). Inhibition of BCRP function followed by an increase in the plasma concentration of BCRP substrate drugs, especially those with a narrow therapeutic index, may lead to adverse reactions [112]. BCRP inhibitors with many different chemical structures have been identified, and many P-gp inhibitors are also known as effective BCRP inhibitors [113]. BCRP inhibitor values were Quercetin (0.995), Curcumin (0.286), CAPE (0.193), Melatonin (0.052), Fexofenadine (0.042), Desloratadine (0.014), Levocetirizine (0.0), Vitamin C (0.103). It can be interpreted that Quercetin, which has the highest BRC inhibition value, can increase plasma levels of BCRP-borne drugs, potentially causing drug interactions. However, when the value of Levocetirizine is examined, its inhibition on BCRP is negligible. This can be interpreted as the fact that levocetirizine does not affect BCRP and the risk of interaction with other drugs is almost zero.

Table 5 Distribution properties of molecules

Metabolism properties of desloratadine, levocetirizine, fexofenadine, CAPE, quercetin, melatonin, curcumin and Vitamin C

The cytochrome P450 (CYP) family of enzymes is the basic enzyme system that performs phase I metabolism of xenobiotics, i.e., pharmaceuticals and environmental toxins. Inhibition and induction of CYP enzymes are among the main causes of pharmacokinetic drug-drug interactions and are involved in the metabolism of 90% of currently available drugs. These enzymes are most commonly found in the liver, but are also expressed in the kidney, placenta, adrenal gland, gastrointestinal tract and skin. Important CYP enzymes such as CYP2C9, CYP2C19, CYP3A4, CYP2D6 and CYP1A2 are particularly examined in silico analyses. The cytochrome P450 (CYP) family of enzymes is the major enzyme system that catalyzes the phase I metabolism of xenobiotics, including pharmaceuticals and toxic compounds in the environment. Inhibition and induction of CYPs are the main mechanisms that cause pharmacokinetic drug-drug interactions, responsible for metabolizing 90% of drugs available today. CYPs are expressed primarily in the liver, kidney, placenta, adrenal gland, gastrointestinal tract and skin. CYP1A2, CYP2C19, CYP3A4, CYP2C9 and CYP2D6, which are important CYPs, are especially analyzed in silico analysis [114,115,116]. Human cytochrome P450 1A2 (CYP1A2) is a metabolizing enzyme usually found in the liver, which metabolizes approximately 20% of clinically used drugs and makes up approximately 13% of the entire CYP protein [117, 118] In humans, cigarette smoking, and rodents, isosafrol and β-naphtoflavones cause CYP1A2 to be induced [119].

When CYP1A2 inhibition values were examined, Melatonin and CAPE (1.0), Quercetin (0.998), Curcumin (0.965), Desloratadine (0.83), Vitamin C (0.01), Levocetirizine and Fexofenadine (0.0) were respectively. The highest inhibition value was CAPE and Melatonin. However, Levocetirizine and Fexofenadine were non-inhibitors for CYP1A2. It can be interpreted that melatonin and CAPE have a complete inhibition effect on CYP1A2, and that these compounds affect the metabolism of other drugs by inhibiting the activity of CYP1A2. However, when Levocetirizine, Fexofenadine, and Vitamin C are examined, the inhibition effects appear to be very low or non-existent. It can be concluded that Levocetirizine, Fexofenadine and Vitamin C do not affect CYP1A2 and have a low risk of interaction (Table 6). CYP2C19 is an important enzyme for estrogen and organophosphate pesticide metabolism Inhibition of CYP2C19 can significantly alter the pharmacokinetics of drugs metabolized by this enzyme, potentially leading to increased plasma levels and prolonged effects, resulting in enhanced therapeutic effects or adverse reactions [120, 121]. When CYP2C9 inhibition values were examined, they were CAPE (0.999), Quercetin (0.432), Curcumin (0.034), Melatonin (0.032), Vitamin C (0.02), Levocetirizine and Fexofenadine (0.0). The CAPE with the highest inhibition value was (Table 6). When CYP2C19 inhibition values were examined, they were CAPE (0.998), Melatonin (0.335), Curcumin (0.257), Quercetin (0.006), Vitamin C, Desloratadine, Levocetirizine, Fexofenadine (0.0). CAPE had the highest inhibition above CYP2C19 (Table 6). CYP2C9, which is inhibited by drugs such as rifampin, amiodarone, fluconazole, and sulfaphenazole, is the enzyme responsible for the metabolism of the S-isomer of warfarin, which is primarily responsible for the anticoagulant effect of the drug [122,123,124]. When the CYP2D6 inhibition values were examined, they were Levocetirizine (0.961), Desloratadine (0.622), CAPE (0.358), Melatonin (0.079), Curcumin (0.025), Vitamin C (0.0), Quercetin and Fexofenadine (0.0), respectively. Levocetirizine had the highest inhibition value. (Table 6). When the CYP3A4 inhibition values were examined, they were Fexofenadine and CAPE (1), Quercetin (0.937), Curcumin (0.885), Melatonin (0.656), Desloratadine (0.225), Levocetirizine and Vitamin C (0.0), respectively. Fexofenadine and CAPE had the highest inhibition value. This means that Levocetirizine and Vitamin C have no effect on the CYP3A4 enzyme or do not have an inhibitory capacity on this enzyme. However, Fexofenadine and CAPE significantly inhibit the activity of the CYP3A4 enzyme, and it can be interpreted that they have effects on the metabolism of both (Table 6). It can be stated that they exhibit a significant inhibitory effect on the CYP1A2, CYP2C19, CYP2C9, and CYP3A4 enzymes.

Table 6 Metabolism properties of molecules

Table 7 Excretion properties of molecules

Excretion properties of desloratadine, levocetirizine, fexofenadine, CAPE, quercetin, melatonin, curcumin and Vitamin C

Drug clearance is defined as the process of drug excretion from the body or a single organ, so drug clearance is important when determining the dosage of drugs. The unit of measurement for drug cleansing, which is defined as the volume of plasma cleared from a drug in a given time period, is usually volume/time (L/h). However, it can also be calculated differently; Clearance is equal to the concentration of a drug in plasma (mg/mL) divided by the rate at which a drug is cleared from plasma (mg/min) [125, 126]. When CLplasma values were examined, they were CAPE (14.184), Curcumin (9.635), Quercetin (8.289), Melatonin (7.852), Desloratadine (6.872), Vitamin C (4.37), Levocetirizine (1.102), Fexofenadine (0.785). It had the highest CAPE value of CLplasma, while Fexofenadine was the lowest. The importance of plasma protein binding lies primarily in its effect on pharmacokinetic properties such as clearance (CL) and volume of distribution (VDs) [127] (Table 7). T1/2 half-life is defined as the time it takes for a drug to decrease the plasma concentration by 50%, and generally periods longer than half an hour are considered a good value; this time is related to the rate constant (k), volume of dispersion (Vd), and cleaning (CL) [128, 129].

T1/2 values were Vitamin C (2.056), Quercetin (1.586), Levocetirizine (1.464), Fexofenadine (1.206), CAPE (1.108), Curcumin (1.196), Desloratadine (0.606), Melatonin (0.839). Desloratadine and Melatonin were found to be ultra-short half-life drugs, while Levocetirizine, Fexofenadine, CAPE, Quercetin, Curcumin, Vitamin C were evaluated as short half-life drugs. It indicates that these compounds are removed from the human body at a reasonable rate. Since the slower the CL, the longer the T1/2 will be, so they are interdependent [130] (Table 7). This means that the compound with a high T1/2 value stays in the body longer and is excreted more slowly, such as Vitamin C. It may also mean that such compounds should be taken less frequently. Desloratadine, on the other hand, has the lowest T1/2 value, so it can be interpreted that it will be excreted from the body faster, but it may require more frequent dosage (Table 7).

Toxicity properties of desloratadine, levocetirizine, fexofenadine, CAPE, quercetin, melatonin, curcumin and Vitamin C

As an important issue for the pharmaceutical industry, the toxicity of drugs is a significant cause of reduction at all stages of drug development [131, 132]. The gene associated with human ether-a-go-go by small molecules (hERG) encodes a voltage-gated potassium channel known as the hERG channel, but blocking the potassium channel can cause serious cardiac side effects (cardiac toxicity, cardiac arrhythmias, and sudden death). It is important to evaluate compounds for activity in hERG channels in the early stages of the drug discovery process, as many drugs have been withdrawn from the market due to severe hERG-cardiotoxicity. Due to the lack of crystal structure of the hERG channel, researchers mostly use the ligand-based drug design approach to identify hERG blockers [133,134,135]. The withdrawal of some FDA-approved drugs for various reasons is due to presumptions that the drugs are hERG blockers with moderate binding affinity and cardiotoxicity issues [122]. When the hERG blockers value was examined, it was Vitamin C (0.008), Quercetin (0.053), Melatonin (0.202), CAPE (0.37), Curcumin (0.41), Desloratadine (0.866), Levocetirizine (0.918), Fexofenadine (0.888). Levocetirizine had the highest value as an hERG blocker, while Vitamin C had the lowest. Vitamin C and Quercetin values are very low or mean a low hERG blockade value, which can be interpreted as having a very low risk of both causing cardiac toxicity, cardiac arrhythmia and sudden death. On the contrary, if a high hERG blockade value is high, it can be interpreted that the risk of cardiac toxicity, cardiac arrhythmia and sudden death may be high (Table 8). Drug-induced liver injury (DILI), which is still an important exclusionary diagnosis, remains a challenge in clinical practice. Drug-induced liver injury is an adverse toxic drug reaction that leads to liver damage. In addition, with the ever-increasing repertoire of medicines combined with changing consumer behavior towards the use of phytotherapy, it is imperative that physicians both recognize and effectively manage DILI [136].

Table 8 Toxicity properties of molecules

When drug-induced liver injury (DILI) values were examined, Quercetin (0.783), Melatonin (0.739), Desloratadine (0.684), Vitamin C (0.383), CAPE (0.115), Levocetirizine (0.012), Fexofenadine (0.003), Curcumin (0.01). Quercetin and Melatonin are considered to have a high potential for liver damage with a high DILI value, while Levocetirizine and Fexofenadine have a very low DILI value, indicating that the risk of liver damage is very low (Table 8). When AMES Mutagenicity values were examined, Melatonin (0.613), Quercetin (0.586), CAPE (0.565), Curcumin (0.411), Desloratadine (0.405), Vitamin C (0.314), Levocetirizine (0.079), Fexofenadine (0.011) were examined. Melatonin had the highest mutagenic property, but it was not very high (medium). Fexofenadine had the lowest mutagenic properties. However, it is important to note that these results may not always fully coincide with clinical use. The AMES mutagenicity test is a biological test used to determine whether new chemicals and drugs are mutagenic. While this test is based on the results of experiments using different strains of Salmonella typhimurium, most of the current in silico models do not estimate mutagenicity, considering the results of separate experiments conducted for each strain [137]. (Table 8) Rat Oral Acute Toxicity, which is important in understanding hazard identification and drug risk management, is usually measured by a 50% lethal dose (LD50); This is the amount of chemicals that are expected to cause death in 50% of treated animals over a given period. LD50 is one of the most important steps in the drug discovery pipeline [138, 139]. When Rat Oral Acute Toxicity values were examined, they were Desloratadine (0.882), Levocetirizine (0.489), Quercetin (0.48), Fexofenadine (0.389), Melatonin (0.253), Curcumin (0.177), CAPE (0.064), Vitamin C (0.046). The higher the Rat Oral Acute Toxicity value, the more likely the compound/molecule is to be toxic. Desloratadine may be considered in the high toxicity category and may be interpreted as requiring caution. In the light of this information, especially CAPE and Vitamin C have very low toxicity (Table 8). When FDA Maximum Recommended Daily Dose (FDAMDD) values were examined, they were Fexofenadine (0.963), Desloratadine (0.84), Melatonin (0.847), Quercetin (0.789), Levocetirizine (0.53), CAPE (0.362), Curcumin (0.325), Vitamin C (0.042). This assessment expresses the compliance of each compound with the maximum daily dose recommendation and the probability of being positive. It shows high compliance in this category, as it is most likely to be fexofenadine positive, so it is very close to the maximum daily dose recommended by the FDA. But because it’s the compound that’s least likely to be Vitamin C positive, it’s very unlikely to adhere to the FDA’s maximum recommended daily dose. Since the FDA’s maximum daily dose recommendations are set to ensure the safe and effective use of drugs and compounds, the use of CAPE, Curcumin, Vitamin C compounds may carry potential health risks and should therefore be carefully evaluated (Table 8) When the carcinogenicity values were examined, Fexofenadine (0.02), Levocetirizine (0.118), Desloratadine (0.198), CAPE (0.221), Curcumin (0.124), Vitamin C (0.356), Melatonin (0.549), Quercetin (0.6). Fexofenadine, Levocetirizine, Desloratadine, CAPE and Curcumin are unlikely to be carcinogenic and generally safe, while Vitamin C, Melatonin and Quercetin are highly likely to be carcinogenic and are not safe (Table 8) When RPMI-8226 Immunotoxicity values were examined, Vitamin C (0.02), Melatonin (0.07), Levocetirizine (0.025), CAPE (0.025), Quercetin (0.023), Fexofenadine (0.039), Desloratadine (0.067), Curcumin (0.105). RPMI-8226. The higher the Immunotoxicity values, the more likely a substance/compound is to be immunotoxic (toxic to the immune system). Vitamin C can be interpreted as safe as Quercetin is very unlikely to be immunotoxic, while Curcumin is more likely to be immunotoxic than others (Table 8).

Table 9 Biological Target of Molecules 

When A549 Cytotoxicity and Hek293 Cytotoxicity values were examined, Vitamin C (0.004; 0.011), Melatonin (0.004; 0.112), Levocetirizine (0.036; 0.347), CAPE (0.477; 0.473), Quercetin (0.582; 0.561), Fexofenadine (0.099; 0.652), Desloratadine (0.582; 0.51), Curcumin (0.628; 0.652). Vitamin C, Melatonin and Levocetirizine cytotoxicity are very unlikely. However, since Curcumin is more likely to cause cytotoxicity in both cell lines, it is likely to damage such cells (Table 8). Knowledge of drug-induced neurotoxicity is essential to develop preventive approaches for neurodegenerative syndromes, as well as preventive measures against neurotoxicity are important [140]. When Drug-induced Neurotoxicity was examined, Desloratadine (0.973), Levocetirizine (0.94), Fexofenadine (0.86) CAPE (0.204), Melatonin (0.715) Curcumin (0.395), Vitamin C (0.033, Quercetin (0.009) were. Desloratadine, followed by Levocetirizine and Fexofenadine, can be interpreted as 97.3%, 94%, 86%, respectively, meaning that Desloratadine, Levocetirizine and Fexofenadine are most likely neurotoxic. However, the probability of Quercetin being neurotoxic is 0.9%, meaning that the probability of Quercetin being neurotoxic is very low. Compounds with low probability values such as Vitamin C and Quercetin can generally be considered safe (Table 8). When the hematotoxicity values were examined, they were Melatonin (0.637), Desloratadine (0.567), Levocetirizine (0.298), Vitamin C (0.171), Fexofenadine (0.049), Curcumin (0.038), Quercetin (0.032), CAPE (0.015). Melatonin had the highest hematotoxicity probability, showing 63.7%, while CAPE had the lowest hematotoxicity probability, showing 1.5%. Melatonin and Desloratadine had a higher hematotoxicity risk than other compounds, while Vitamin C, Fexofenadine, Curcumin, Quercetin and CAPE stood out with their very low risk levels (Table 8).

Identification of the biological target of molecules (druggability)

Among these compounds, the strongest biological effect was Vitamin C on Dengue larvicida, while CAPE on Epimastigote Chagas. This can be interpreted as Vitamin C and CAPE have strong effects on certain biological targets. Desloratadine, which generally has Active, probability; 06–08 values, affected the most biological target. Desloratadine was active on biological targets such as Sars-Cov, E_coli, C_albicans, Dengue larvicida, Salmonella, Hepatite C—Type1, Leishmania infantum—Promastigota. Fexofenadine also turned out to be an unreliable target on Salmonella. These findings mean that Desloratadine has a wide range of biological targets [47] (Table 9).

Identification of the biological activity of molecules

The chances of finding a particular activity experimentally increase with an increase in the value of Pa and a decrease in the value of Pi. To obtain the biological significance of the compounds present, we used the PASS online server to estimate their different bio-activities. The threshold of probability of being active (Pa) against different activities was kept at > 0.7 in order to select the best activities. The compounds showed promising biological activities in PASS predictions, suggesting potential therapeutic or research applications in a variety of pharmacological targets. The top 5 activities that appeared in the results were put in Table 10. Desloratadine (Pa: 0.771) Nicotinic alpha2beta2 receptor antagonist, Levocetirizine (Pa: 0.909) Antieczematic, Fexofenadine (Pa: 0.819) P-glycoprotein substrate, CAPE (Pa: 0.948) Membrane integrity agonist, Quercetin (Pa: 0.973 Membrane integrity agonist, Melatonin (Pa: 0.914) 5 Hydroxytryptamine release stimulant, Curcumin (Pa: 0.936) Feruloyl esterase inhibitor, Vitamin C (Pa: 0.948) Vasoprotector show good biological activity [40] (Table 10). Although this study did not directly perform experimental testing of the PASS prediction results, literature data on such activity in molecular analogues were presented as indirect evidence for the accuracy of the prediction. The PASS online results also reveal that these compounds have some potential biological activities and could be a potential resource for the development of drugs in the future [141].

Table 10 Biological activities of molecules via PASS server

Molecular docking method

Desmoglein 1 protein–ligand docking results

In this study, the binding energies (Gibbs free energies, ΔG) and H bond and hydrophobic interactions resulting from ligand–protein interaction with the ‘compounds in Table 1 and Desmoglein-1(AF-Q02413-F1) structure’ are shown in Table 2. The negative value of ΔG results indicates that the reaction is exothermic and occurs voluntarily. The best binding was observed in Quercetin > Fexofenadine > Desloratadine > Curcumin > CAPE > Levocetirizine > Melatonin > Vitamin C. Our results include hydrogen bond interaction, hydrophobic and electrostatic interaction in Table 11. It is the best binding conformation region of the ligand (the molecule under investigation) structure to the protein active site in molecular docking analysis. The best conformation regions obtained in molecular docking analysis are given in Fig. 2. As shown in Fig. 3, the two-dimensional bond interactions of molecular docking are shown. These bond interactions were performed with the ligand structures having the best binding confo rmation to the Desmoglein 1 structure. The ligands presented in Fig. 3 were bound to the Desmoglein 1 protein structure. Figure 3A shows the bonds between the CAPE ligand and the protein: conventional hydrogen, carbon hydrogen bond, pi-pi and pi-alkyl, Fig. 3B shows the curcumin ligand: conventional hydrogen, carbon hydrogen bond, pi-pi, pi alkyl, pi alkyl, amide pi, alkyl, Fig. 3C shows the vitamin c ligand: conventional hydrogen only, Fig. 3D shows the desloratadine: pi-pi, pi-alkyl and alkyl, fexofenadine ligand in Fig. 3E made conventional hydrogen, carbon hydrogen, alkyl, pi alkyl, pi sigma, amide pi, pi p, levocetirizine ligand in Fig. 3F made carbon hydrogen and pi alkyl, melatonin in Fig. 3G made pi pi and pi alkyl, and quercetin ligand in Fig. 3H made conventional hydrogen, pi cation and pi-pi bonds.

Table 11 Molecular docking data for Desmoglein 1

Fig. 2

The best conformational regions obtained for Desmoglein 1 in molecular docking analysis (A CAPE, B Curcumin, C Vitamin C, D Desloratadine, E Fexofenadine, F Levocetirizine, G Melatonin and H Quercetin)

Fig. 3

Ligand binding structures obtained for Desmoglein 1 in molecular docking analysis: (A CAPE, B Curcumin, C Vitamin C, D Desloratadine, E Fexofenadine, F Levocetirizine, G Melatonin and H Quercetin)

Human histamine H1 receptor protein ligand docking results

In this study, the binding energies (Gibbs free energies, ΔG) and H bond and hydrophobic interactions resulting from ligand–protein interaction with the ‘compounds in Table 1 and Human Histamine H1 Receptor (PDB ID: 3RZE) structure’ are shown in Table 2. The negative value of ΔG results indicates that the reaction is exothermic and occurs voluntarily. The best binding was observed for Fexofenadine > Desloratadine > Levocetirizine > Quercetin > Melatonin > Curcumin > CAPE > Vitamin C. Our results include hydrogen bond interaction, hydrophobic and electrostatic interaction in Table 12. The best conformation regions between human histamine H1 receptor-compounds obtained in molecular docking analysis are given in Fig. 4. The ligands presented in Fig. 5 were bound to the Human Histamine H1 Receptor protein structure. Figure 5A shows the bonds between the CAPE ligand and the protein: carbon hydrogen, pi pi, pi alkyl, pi alkyl, pi sulphur, Fig. 5B ‘ curcumin ligand conventional hydrogen, pi-pi, pi alkyl, alkyl, Fig. 5C’ vitamin conventional hydrogen, Fig. 5D' desloratadine pi pi, alkyl, pi alkyl, fexofenadine ligand conventional hydrogen, alkyl, pi alkyl, pi alkyl, pi pi in Fig. 5E, levocetirizine ligand alkyl, pi alkyl, pi pi pi in Fig. 5F, melatonin carbon hydrogen, pi sigma, pi alkyl in Fig. 5G and quercetin ligand conventional hydrogen, pi cation, pi alkyl and pi-pi bonds in Fig. 5H.

Table 12 Molecular docking data for Human Histamin H1 Receptor

Fig. 4

The best conformational regions obtained for Human Histamine H1 Receptor in molecular docking analysis (A CAPE, B Curcumin, C Vitamin C, D Desloratadine, E Fexofenadine, F Levocetirizine, G Melatonin and H Quercetin)

Fig. 5

.Ligand binding structures obtained for Human Histamine H1 Receptor in molecular docking analysis: (A CAPE, B Curcumin, C Vitamin C, D Desloratadine, E Fexofenadine, F Levocetirizine, G Melatonin and H Quercetin)

IgE protein ligand docking results

In this study, the binding energies (Gibbs free energies, ΔG) and H bond and hydrophobic interactions resulting from ligand–protein interaction with the ‘compounds in Table 1 and IgE (PDB ID: 3H9Y) structure’ are shown in Table 2. The negative value of ΔG results indicates that the reaction is exothermic and occurs voluntarily. The best binding was observed in Fexofenadine > Quercetin > Desloratadine > Curcumin > Levocetirizine > CAPE > Melatonin > Vitamin C. Our results include hydrogen bond interaction, hydrophobic and electrostatic interaction in Table 13. The best conformation regions between IgE-compounds obtained in molecular docking analysis are given in Fig. 6. Molecular docking two-dimensional bond interactions are shown in Fig. 6. These bond interactions were performed with the ligand structures having the best binding conformation to the IgE structure. The ligands presented in Fig. 7 were bound to the IgE protein structure. Figure 7A shows the bonds between the CAPE ligand and the protein: conventional hydrogen, pi donor hydrogen bond, carbon hydrogen, pi alkyl, Fig. 7B’ Curcumin ligand conventional hydrogen, pi donor hydrogen bond, pi alkyl, pi anion, Fig. 7C’ Vitamin C conventional hydrogen, carbon hydrogen, Fig. 7D' Desloratadine pi pi, pi sigma, Fexofenadine ligand conventional hydrogen, pi alkyl, pi sigma, pi anion in Fig. 7E, Levocetirizine ligand conventional hydrogen, carbon hydrogen, pi alkyl, pi pi pi, Melatonin carbon hydrogen, pi anion, pi alkyl in Fig. 7G and Quercetin ligand conventional hydrogen, pi cation, pi alkyl and pi sigma bonds in Fig. 7H.

Table 13 Molecular docking data for IgE

Fig. 6

The best conformational regions obtained for IgE in molecular docking (A CAPE, B Curcumin, C Vitamin C, D Desloratadine, E Fexofenadine, F Levocetirizine, G Melatonin and H Quercetin)

Fig. 7

Ligand binding structures obtained for IgE in molecular docking analysis: (A CAPE, B Curcumin, C Vitamin C, D Desloratadine, E Fexofenadine, F Levocetirizine, G Melatonin and H Quercetin)

IL13 protein ligand docking results

In this study, the binding energies (Gibbs free energies, ΔG) and H bond and hydrophobic interactions resulting from ligand–protein interaction with the ‘compounds in Table 1 and IL13 (PDB ID: 1IJZ) structure’ are shown in Table 2. The negative value of ΔG results indicates that the reaction is exothermic and occurs voluntarily. The best binding was observed in Fexofenadine > Quercetin > Desloratadine > Curcumin > Levocetirizine > CAPE > Melatonin > Vitamin C. Our results include hydrogen bond interaction, hydrophobic and electrostatic interaction in Table 14. The best conformation regions between IL13-compounds obtained in molecular docking analysis are given in Fig. 8. As shown in Fig. 9, two-dimensional bond interactions of molecular docking are observed. These bond interactions were performed with the ligand structures having the best binding conformation to the IL13 structure. The results of the molecular docking study showed that among Desloratadine, Levocetirizine Fexofenadine, CAPE, Quercetin, Melatonin, Curcumin and Vitamin C compounds targeted to Desmoglein 1, Human H1 receptor, IgE and IL13 protein structures, Fexofenadine and Quercetinshowed the best binding affinity against all proteins. Vitamin C had the least binding affinity among the compounds. In Desmoglein 1, the order of binding affinity was Quercetin > Fexofenadine > Desloratadine > Curcumin > CAPE > Levocetirizine > Melatonin > Vitamin C. The order in Human Histamine H1 Receptor was Fexofenadine > Desloratadine > Levocetirizine > Quercetin > Melatonin > Curcumin > CAPE > Vitamin C. According to IgE binding order; Fexofenadine > Quercetin > Desloratadine > Curcumin > Levocetirizine > CAPE > Melatonin > Vitamin C. The order of IL13 binding was Fexofenadine > Quercetin > Desloratadine > Curcumin > Levocetirizine > CAPE > Melatonin > Vitamin C.

Table 14 Molecular docking data for IL13

Fig. 8

The best conformational regions obtained for IL13 in molecular docking (A CAPE, B Curcumin, C Vitamin C, D Desloratadine, E Fexofenadine, F Levocetirizine, G Melatonin and H Quercetin)

Fig. 9

Ligand binding structures obtained for IL13 in molecular docking analysis: (A CAPE, B Curcumin, C Vitamin C, D Desloratadine, E Fexofenadine, F Levocetirizine, G Melatonin and H Quercetin)

DFT calculations

DFT calculations provide important insights into the electronic properties of molecules, aiding in the prediction of chemical reactivity and stability. The energy gap (ΔE) between HOMO and LUMO was calculated, offering a measure of a molecule's electronic stability and reactivity. Electrophilicity(ω), nucleophilicity (Nu), hardness (η), electronegativity (χ) and softness (s) were also assessed. The dipole moment (μ), which indicates the distribution of charge within the molecule, was measured as well. In Table 15 and Fig. 10 Desloratadine, with an energy gap of 1.10 eV, demonstrates notable electronic instability compared to other molecules in the study. This small ΔE suggests higher chemical reactivity. Its high softness which is 1.81 eV⁻¹ and low hardness which is 0.55 eV, further support its reactive nature, while its dipole moment of 5.4972 Debye indicates significant charge separation, potentially influencing its interactions with biological targets. Levocetirizine presents a much larger energy gap of 3.69 eV, indicating greater electronic stability and lower reactivity. Its hardness (1.85 eV) and softness (0.54 eV⁻¹) reflect a stable molecular structure. The relatively lower dipole moment of 2.7238 Debye suggests less pronounced charge separation within the molecule, which may impact its pharmacological interactions. Fexofenadine shows an intermediate energy gap of 3.30 eV, suggesting moderate stability and reactivity. The hardness is 1.65 eV and softness is 0.61 eV⁻¹, these values align with its electronic characteristics. A dipole moment of 2.0100 Debye indicates moderate charge separation, potentially affecting its solubility and binding affinity. Caffeic acid phenethyl ester, with an energy gap of 3.38 eV, demonstrates balanced stability and reactivity. Its softness (0.59 eV⁻¹) hardness (1.69 eV) are consistent with these properties. The low dipole moment of 0.7940 Debye indicates minimal charge separation, which could influence its bioavailability and interaction with targets. Vitamin C displays the largest energy gap of 4.65 eV, suggesting significant electronic stability and minimal reactivity. Its high hardness (2.33 eV) and low softness (0.43 eV⁻¹) further confirm this stability. The dipole moment of 10.4052 Debye is notably high, indicating substantial charge separation, which may affect its solubility and interaction dynamics. Quercetin, with an energy gap of 3.97 eV, shows considerable stability and reduced reactivity. Its hardness (1.99 eV) and softness (0.50 eV⁻¹) align with its stable electronic nature. The dipole moment of 3.3798 Debye indicates a moderate degree of charge separation, influencing its biochemical interactions. Curcumin exhibits a lower energy gap of 2.83 eV, indicating higher reactivity. Its hardness is 1.41 eV and softness is 0.71 eV⁻¹, these values reflect a more reactive nature. The dipole moment of 2.7379 Debye suggests moderate charge separation, which could impact its binding and solubility. Melatonin, with an energy gap of 4.89 eV, has the highest electronic stability and the lowest reactivity among the molecules studied. Its high hardness (2.44 eV) and low softness (0.41 eV⁻¹) further support this stability. The dipole moment of 2.2119 Debye indicates a moderate degree of charge separation, which may influence its interaction with biological systems.

Table 15 The obtained parameters by DFT/B3LYP/6-311G (++ d,p) for all molecules

Fig. 10

Compounds structures of a Desloratadine, b Levocetirizine, c Fexofenadine, d CAPE, e Vitamin C, f Quercetin, g Curcumin and h Melatonin

Consequently, the Structure–Activity Relationship (SAR) analysis reveals that molecules with smaller energy gaps (ΔE) exhibit higher chemical reactivity, as observed in Desloratadine (1.10 eV) and Curcumin (2.83 eV). These compounds also demonstrate higher softness and lower hardness, indicating their potential to interact more readily with biological targets. Conversely, molecules with larger ΔE values, such as Melatonin (4.89 eV) and Vitamin C (4.65 eV), are electronically stable and less reactive. Dipole moments provide additional insights into charge distribution, influencing solubility and binding potential. For example, the high dipole moment of Vitamin C (10.4052 Debye) suggests strong polar interactions, while the low dipole moment of CAPE (0.7940 Debye) may reduce its aqueous solubility.

Conclusion

Melatonin demonstrated the highest Caco-2 permeability, while Desloratadine exhibited the most favorable PAMPA value. Levocetirizine displayed high bioavailability, whereas Curcumin showed low bioavailability. Both Vitamin C and Melatonin presented moderate bioavailability. PPB values indicated optimal levels for Quercetin, CAPE, and Curcumin. Notably, Curcumin and CAPE exhibited strong inhibitory effects on OATP1B1 and OATP1B3 transporters, whereas Levocetirizine and Fexofenadine had minimal effects, suggesting varying implications for drug transport and interaction potential. Quercetin emerged as the strongest BCRP inhibitor, raising concerns about potential drug interactions due to increased plasma levels. In contrast, Levocetirizine’s minimal effect on BCRP suggests a lower risk of such interactions. High inhibition of CYP1A2 by Melatonin and CAPE highlights their potential to interfere with the metabolism of co-administered drugs, while Levocetirizine, Fexofenadine, and Vitamin C appeared inactive against this enzyme. CAPE also exhibited significant inhibition of CYP2C19 and CYP2C9, which could alter plasma concentrations of drugs metabolized by these enzymes, whereas Levocetirizine and Fexofenadine were the most potent CYP3A4 inhibitors. Interestingly, Levocetirizine demonstrated the strongest inhibition of CYP2D6. The toxicity profiles revealed that Vitamin C and Quercetin are safer regarding cardiac toxicity and mutagenic risks, whereas Desloratadine and Levocetirizine posed higher risks of neurotoxicity and hematotoxicity. CAPE, with its high enzyme inhibition activity and low toxicity, stands out as a compound with promising therapeutic potential. However, hERG blockade, DILI, and cytotoxicity values for other compounds underline safety concerns that require further evaluation. Docking studies underscored significant ligand–protein interactions, with Desloratadine, Levocetirizine, Fexofenadine, CAPE, Quercetin, Melatonin, Curcumin, and Vitamin C exhibiting good binding affinities toward Desmoglein 1, Human Histamine H1 receptor, IgE, and IL-13 proteins. Notably, Fexofenadine and Quercetin demonstrated the strongest binding affinities, supporting their potential efficacy. Complementary DFT analyses highlighted distinct electronic properties across the molecules, providing insights into their chemical reactivity and potential applications; Desloratadine (ΔE = 1.10 eV) and Curcumin (ΔE = 2.83 eV) showed high reactivity due to smaller energy gaps, aligning with their biological activity and enzyme inhibitory effects. In contrast, Melatonin (ΔE = 4.89 eV) and Vitamin C (ΔE = 4.65 eV) demonstrated remarkable electronic stability, correlating with moderate bioavailability and reduced risk of interactions. High dipole moments, such as in Vitamin C (10.4052 Debye), reflected strong charge separation, which may enhance solubility and protein interactions. Lower dipole moments, as observed in CAPE (0.7940 Debye), suggested reduced aqueous solubility but notable enzyme inhibition, particularly of CYP2C19 and CYP2C9. The balanced reactivity and moderate dipole moments of Vitamin C and Quercetin align with their safer toxicity profiles, emphasizing their potential for therapeutic use with minimal risks. The binding of histamine to the extracellular portion of the H1 receptor triggers a structural change of the transmembrane portion, leading to a change in the C terminal area. Target mechanisms of histaminic receptor drugs usually involve hydrophobic interactions. These interactions play an important role in the binding of drug molecules with receptors. Interactions of drugs and receptors include covalent, ionic, hydrophobic and van der Waals binding. It is hypothesised that this may be attributed to the low affinity of the vitamin C compound, which is only capable of forming hydrogen bonds [142, 143].