Drug likeness Properties ADME/T Analysis and Thrombolytic Activity of Phenolic Compounds in Allium sativum peel Extract - In-silico Approach

M. Nagabharathi¹*, Sampara Meera Bai²

¹Associate Professor, Department of Pharmacology, Vignan Institute of Pharmaceutical Technology,

Duvvada, Visakhapatnam, Andhra Pradesh, India.

²M.Pharm Student, Department of Pharmacology, Vignan Institute of Pharmaceutical Technology,

Duvvada, Visakhapatnam, Andhra Pradesh, India.

*Corresponding Author E-mail: bharathimarni@gmail.com

ABSTRACT:

Phytochemicals are significant in the drug development, Allium sativum perennial herb distributed in Tropical Asia, it was commonly called Garlic. Its peel had various medicinal properties such as Cytotoxicity, Anti bacterial and Anti-inflammatory. Hence peel was also exploded for thrombolytic effect. Current work was performed to identify different phytochemicals in Ethanolic garlic peel extract (Allium sativum) based on previous literature and to perform molecular docking with Protein tissue plasminogen activator (tPA) for their potential thrombolytic activity, to analyze their drug similarity and also ADME/T profiles. Literature from 2010 to 2023 was searched for reported phenolic phytochemicals of peel extract. Four compounds i.e Caffeic acid, P-Coumarin, Ferulic acid, Di-ferulic acid were selected, Study focused on the molecular interactions between four phytochemical compounds selected as ligands. Their 2D structures were downloaded from Pub Chem Database in SDF format and later converted to PDB format by Openbabel tool and Tissue plasminogen activator (tPA) which is involved in the coagulation cascade, was selected as Protein, it’s structure was downloaded from Protein data bank in PDB format. Docking was done using Argus lab version.4. The grid box size was set at 151, 151, and 151 Å (x, y, and z). Caffeic acid, P-coumarin, ferulic acid and diferulic acid docked within the binding pocket tPA with binding energies of −9.17757kcal/mol, − 8.69086 kcal/mol, −8.42909kcal/mol and − 8.97502 kcal/mol. Among all ligands, caffeic acid interacted with largest number (20) of residues within the target molecule. In contrast, P-coumarin interacted with (8) amino acid residues, ferulic acid with (20) amino acid residues and diferulic acid with (18) amino acid residues. Caffeic acid has a better point of contact with low binding energies. Later ADME/T analysis for all compounds was performed using SWISS ADME/T. Caffeic acid, P-coumarin, Ferulic acid, and Diferulic acid obeyed Lipinski's rule of five, Furthermore, Caffeic acid showed good drug similarity Property and the ADME/T profiling predicted that it was safe can be consumed by humans. However, further in - vivo studies might be needed for confirmation of the thrombolytic activity of caffeic acid.

KEYWORDS: Allium sativum, In-silico, ADME/T, Thrombolytic activity, Garlic, Docking.

INTRODUCTION: 

Thrombosis is a condition where blood clots were formed in the circulatory system and can occur in veins or arteries ¹. These blood clots can restrict flow of blood and lead serious complications include pulmonary embolism, stroke, atherosclerosis and heart attack ².

Figure 1: Formation of Thrombosis ¹

Thrombosis results from an imbalance between clotting and anticoagulation (preventing blood clots) in the blood. Blood clots usually form in response to injury to blood vessels and help to stop bleeding. However, certain factors can cause blood clots to form without causing any obvious damage³.

Treatment of thrombosis usually includes the use of anticoagulants (blood thinners) to prevent further clots from forming and to allow existing clots to dissolve through the body's natural processes. Specific therapeutic approaches depend on the type of thrombosis, disease severity, patient general condition, and underlying disease ^4.5. Traditionally natural compounds are used as thrombolytics by all ethnicities around the world. Allium sativum commonly known as garlic, it is among herbs which are used to reduce various risk factors associated with diabetes and cardiovascular disease ⁶. Garlic belongs to the Liliaceae family and garlic was popular food as a flavoring and spice. It was commonly used herbs in modern folk medicine⁷.

Mechanism of tissue plasminogen activator (tPA) action in thrombosis:

 In vivo mechanism of action of Tissue plasminogen activator (tPA) in the fibrinolytic system. tPA is transported in the body in three ways. (1) Taken up by the liver and degraded in the liver via receptors ⁸, (2) Inhibited by plasminogen activator inhibitors (PAI) and then transported out of the liver ^9,10, or (3) Plasminogen is activated to plasmin, leading to fibrin degradation products (FDPs) that trigger degradation ^11,12,13.

Figure 2: Role of Tissue plasminogen activator in clot formation ¹¹

In - Silico Docking Study and ADME/T Analysis:

In silico docking studies are used in molecular biology and drug discovery to study, predict and analyze interactions between small molecules (ligands) and bimolecular protein targets (receptors). It is a computational technique The term "in silico" refers to conducting experiments using computational methods on a computer, as opposed to "in vitro" (laboratory) or "in vivo" (living organisms)¹⁴.

The docking process simulates binding of a ligand to a receptor and interprets binding affinity and orientation of ligand in active site of the receptor. This information is valuable in understanding the molecular basis of ligand-receptor interactions, which is essential for drug design, virtual screening, and lead optimization ¹⁵.

The four phases of the pharmacokinetic phase are excretion, distribution, metabolism, and absorption (ADME). It was recently expanded to include a phase for the toxicological assessment of novel drug candidates, which produced the ADME-T research. Providing a competitive product with sufficient safety and efficacy is the main objective in order to prevent PK-based clinical failures. Evaluating the ADME qualities of a medicine in people is a significant difficulty in drug development. A drug candidate's pharmacokinetic profile is analyzed in vitro and in vivo by evaluating its metabolites, permeability, solubility, and absorption, among other variables¹⁶ .

In this study, four compounds derived from garlic (Caffeic acid, P-Coumarin, Ferulic acid, and Di ferulic acid (Figure 3)) were screened for their potential interaction with tPA (Figure 4) and their thrombolytic activity was evaluated. Subsequently, drug-like properties and ADME/T profiles Analyzed for selected ligand molecules. However, confirming the thrombolytic activity of garlic plant compounds requires further in vivo experiments, which were not performed in this study^17.

MATERIALS AND METHODS:

Docking can execute the outcome and suggest structural hypotheses of how target is repressed by ligand that is vital in lead optimization ¹⁸. Argus Lab Version.4 and Pub chem. were used as analytical platforms for this experiment, The optimal position for ligand preparation and ligand-target interaction was determined using docking tool Argus Lab version 4 (Figure 5). The 2D structures of the ligands were refined using Pub chem. (Figure 3).

Figure 3:3D Representation of tPA (PDB ID: 1A5H), ligand-bound form. ¹⁹. The four chains of tPA are shown in ribbon style and the ligand is shown in stick style ²⁰

Caffeic acid (C9H8O4)                                                               p-Coumarin (C9H6O2)

Ferulic acid (C10H10O4)                                                              Diferulic acid (C20H18O8)

Figure 4: 3DChemical structures of Ligands (1) Caffeic acid (Pub chem CID: 689043), (2) P-Coumarin (Pub chem CID: 323) (3) Ferulic acid (Pub chem CID: 44588), (4) Diferulic acid (Pub chem CID: 5281770)

Protein preparation:

Three-dimensional structure of tissue plasminogen activator (Figure 4) (PDB ID: 1A5H) was downloaded in PDB format from protein database (http:http://www.rcsb.org). The protein then produced and purified using the Argus Lab docking tool at protein preparation site. All water molecules were quenched and seleno methionine was converted to methionine. Bond orders were assigned and hydrogen’s were added to the heavy atoms. Finally, structure was optimized and minimized using Argus Lab version 4²¹.

Ligand preparation:

The 2D structure of caffeic acid (Pub chem. CID: 689043), P-coumarin (Pub chem. CID: 323), Ferulic acid (Pub chem. CID: 44588), Diferulic acid (Pub chem. CID: 5281770) was downloaded from pub chem. & shown in figure 5. (http//www.pubchem.ncbi.nlm.nih.gov)²². These structures were converted form SDF format in to PDB format by Open Bable converter²³.

Drug Likness prediction using Lipinski Rule of Five:

By using the Lipinski Rule of Five servers, the oral drug likeness filter test was conducted for above 4 phytochemical compounds based on rule of Lipinski's. Christopher A Lipinski expressed four rules to determine whether a compound could be orally consummate or not: First rule – molecular weight ≤ 500, second rule - partition coefficient (logP) ≤ 5, third rule - number of hydrogen bond donors (HBD) ≤ 5, fourth rule - number of hydrogen bond acceptors (HBA) ≤ 10. He also stated that the compound should not violate more than 2 rules, if it violates then compounds fails in the absorption process during consumption²⁴.

Ligand based drug likeness property and ADME/Toxicity prediction:

The Swiss ADME service (http://www.swissadme.ch/) was used to examine each ligand in order to determine whether or not Lipinski's rule of five is being followed. The ORISIS Property Explorer was utilized to recalculate the ligand molecule's various physicochemical properties²⁵. Table 2 displays the findings from the examination of the characteristics of drug similarity.The ADME/T test for each ligand molecule is available on the web-based server admet SAR (http://immd.ecust.edu.cn/admetsar1/predict/) to predict different pharmacokinetic and pharmacodynamic properties of, among other things, blood barrier permeability, human intestinal absorption, cytochrome P(CYP) inhibition ability, carcinogenicity, mutagenicity, and Caco-2 permeability.²⁶ All ligand compounds' ADME/T findings are displayed in (Table 3).

RESULTS:

Table 1: docking results of (1) Caffeic acid (Pub chem CID: 689043), (2) P-Coumarin (Pub chem CID: 323) (3) Ferulic acid (Pub chem CID: 44588), (4) Diferulic acid (Pub chem)

Compound names	Pub Chem CID	Docking and binding energy (kcal/mol)	Residues Involved In The Hydrogen Bonds,Distance (A^0)	Interacting resuides of target
Caffeic acid	689043	-9.17757 kcal/mol	Leu 130,2.900 Val 231, 2.942 The232,2.722	His57, Tyr99, Asp189, Pro225, Gly226, Val227 Tyr228.Ala190, Cys191, Gln192 Gly193, Ser195, Ile213 Ser214, Trp215, Gly216,Leu217 Gly219,Cys220, Gly221
p-coumarin	323	-8.69086 kcal/mol	Val395,Cys371,2.941 Leu 397,Thr369,2.999, Arg 369,2.256 Leu365,Gln364,2.258 Leu461,Met415,2.263, Trp 368, 2.612 Leu 434, Pro433,2.269 Thr 443, Cys436,2.768 Cys 436,Thr443,2.851 Val 445,Leu444, 2.240 Tyr 462,Val461, 2.260	Phe40, Leu41, Cys42 His57, Cys58, Gln60 Tyr99, Tyr151.
Ferulic acid	445858	-8.42909 kcal/mol	Thr410, 2.791 Tyr 334, 2.708	His57, Tyr99 Gly219, Cys220, Val224 Pro225, Gly226, Val227 Tyr228., Asp189, Ala190, Cys191, Gln192, Gly193, Ser195, Ile213, Ser214, Trp215,Gly216,Leu217
Di ferulic acid	5281770	-8.97502 kcal/mol	Arg73, 2.769 Pro149, 2.898 Lys143, 2.297	Leu181, Cys182, Leu209, Val210, Thr229 Lys230, Val231, Thr232 Asn233. Pro124, Leu128, Gln129 Leu130, Pro131, Asp132 Leu162, Tyr163, Ser165

Caffeic Acid Hydrogen Bonds                                                         Caffeic Acid Molecular Surface Interaction

P-Coumarin Hydrogen bonds                                                           P-Coumarin Molecular Surface Interaction

Ferulic Acid Hydrogen Bonds                                                            Ferulic Acid Molecular Surface Interaction

Diferulic Acid Hydrogen Bonds                                      Diferulic Acid Molecular Surface Interaction

Figure 5: Molecular Docking of Tissue Plasminogen Activator (tPA) with Caffeic acid, P Coumarin, Ferulic acid, Diferulic acid

                                         Caffeic Acid                                                                                                       P-Coumarin

                                        Ferulic Acid                                                                                                   Diferulic Acid

Figure 6: ligand interactions with (tPA) Compounds Like Caffeic Acid, P-Coumarin, Ferulic Acid, Diferulic Acid

Binding energy:

All ligand molecules were docked to protein molecules. The grid box size was set at 151, 151, and 151 Å (x, y, and z). Caffeic acid, P-coumarin, ferulic acid and diferulic acid docked within the binding pocket tPA with binding energies of −9.17757kcal/mol, −8.69086 kcal/mol, −8.42909kcal/mol and −8.97502kcal/mol (table 1). Among all ligands, caffeic acid interacted with the largest number (20) of residues within the target molecule. In contrast, P-coumarin interacted with (8) amino acid residues, ferulic acid with (20) amino acid residues and diferulic acid with (18) amino acid residues of the target molecule. (Fig. 5)²⁷.

Caffeic acid and formed 3 hydrogen bonds each with Leu 130,Val 231,The232, 2.900, 2.942 and 2.722A⁰ distance apart respectively from the corresponding amino acid residue of target molecules, P-Coumarin formed 20 hydrogen bonds each with Val395, Cys371, Leu 397, Thr369, Arg369, Leu365, Gln364, Leu461, Met415, Trp368, Leu434, Pro433, Thr443, Cys436, Cys 436, Thr443, Val445, Leu444, Tyr 462, Val461 and 2.941, 2.999, 2.256, 2.258, 2.263, 2.612, 2.269, 2.768, 2.851, 2.240, 2.260A⁰ distance apart respectively from the corresponding amino acid residue of target molecules, Feruilic acid formed 2 hydrogen bonds each with Thr410, tyr334 and 2.791, 2.708A⁰ distance apart respectively from the corresponding amino acid residue of target molecules, Diferulic acid formed 3 hydrogen bonds each with Arg 73, Pro49, Lys 143, 2.769, 2.898, 2.297, in the binding pocket backbone of tPA²⁸ .

Drug – likeness property:

Table 2: Comparison of drug likeness properties of Caffeic acid (Pub chem CID: 689043), (2) P-Coumarin (Pub chem CID: 323) (3) ferulic acid (Pub chem CID: 44588), (4) Diferulic acid (Pub chem CID: 5281770). Lipinski’s rule of five: molecular weight:<500, number of H-bonds:≤5;Number of H-bond acceptors: ≤10;Lipophilicity (expressed as Log P):<5;and Molar refractivity:40-130.

Drug likeness properties	Caffeic acid	P-Coumarin	Ferulic acid	Di ferulic acid
Molecular Weight	180.16 g/mol	146.14 g/mol	194.18 g/mol	386.35 g/mol
Log P	0.97	3.36	1.62	2.47
Log S	-1.89	-4.32	-2.11	-3.78
H-Bond Acceptor	4	2	4	8
H-Bond Donor	3	0	2	4
Molar Refractivity	47.16	42.48	51.63	102.25
Heavy Atoms	13	11	14	28
Polar Surface Area	77.76	30.21	66.76	133.52
Rotatable Bond	2	0	3	7
Drug Likeness Score	0.56	0.55	0.85	0.56
Drug Score	0.86	0.18	0.36	0.59

In terms of molecular weight (tolerance: <500), number of hydrogen bond donors (tolerance: ≤5), number of hydrogen bond acceptors (tolerance: ≤10), lipophilicity (expressed as log p, tolerance: ≤5), and molar refraction (40-130), caffeineic acid, P-coumarin, ferulic acid, and diferulic acid all complied with Lipinski's rule of five. (Table 2). Diferulic acid has the most topological polar surface area (133.52) of all the ligand molecules, while p-coumarin has the smallest polar surface area (30.21). Conversely, the moderate polar surface areas of ferulic acid and caffeic acid are 66.76 and 77.76, respectively. Compared to the other three chosen ligand molecules, which showed acceptable log S values, caffeineic acid had an extremely low log S value (-1.89). The compounds with the highest drug-likeness scores were caffeic acid and ferrulic acid. Other ligands showed nearly similar drug similarity and drug scoring ²⁹.

ADME/T Test

Table 3: ADME/T properties of Caffeic acid (Pub chem CID: 689043), (2) P-Coumarin (Pub chem CID: 323) (3) ferulic acid (Pub chem CID: 44588), (4) Diferulic acid (Pub chem CID: 5281770). BBB+: Capable of penetrating blood brain barrier; HIA+: Highly absorbed in human intestinal tissue; Caco-2+: Permeable through the membrane of Caco-2 cell lines; CYP450: Cytochrome P450

Properties	Caffeic acid	P-Coumarin	Ferulic acid	Di ferulic acid
Blood-Brain Barrier	BBB-	BBB+	BBB-	BBB-
Human Intestinal Absorption	HIA+	HIA+	HIA+	HIA+
Carcinogens	Non -carcinogens	Non -carcinogens	Non -carcinogens	Non -carcinogens
P-glycoprotein Substrate	Non -substrate	substrate	Non - substrate	Non - substrate
CYP450 2C9 Substrate	Non -substrate	Non-Substrate	Non-Substrate	Non – substrate
Caco-2 Permeability	Caco2+	Caco2+	Caco2+	Caco2+
CYP450 3A4 Substrate	Non -substrate	substrate	Non-Substrate	Non – substrate
CYP450 1A2 Substrate	Non-inhibitor	inhibitor	Non - inhibitor	Non – inhibitor
CYP450 2D6 Substrate	Non -substrate	Non-Substrate	Non-Substrate	Non – substrate
CYP450 2D6 Inhibitor	Non-inhibitor	inhibitor	Non - inhibitor	Non – inhibitor
CYP450 2C19 Inhibitor	Non-inhibitor	inhibitor	Non - inhibitor	Inhibitor
CYP450 2C9 Inhibitor	Non-inhibitor	Non - inhibitor	Non - inhibitor	Inhibitor
CYP450 3A4 Inhibitor	Non-inhibitor	Non-inhibitor	Non - inhibitor	Non – inhibitor
CYP Inhibitory Promiscuity	Low CYP inhibitory promiscuity	Highly CYP inhibitory promiscuity	Low CYP inhibitory promiscuity	Low CYP inhibitory promiscuity
AMES Toxicity	Non AMES toxic	Non AMES toxic	Non AMES toxic	Non AMES toxic
Carcinogenicity (Three-Class)	NON - REQUIRED	NON - REQUIRED	NON - REQUIRED	NON - REQUIRED
Biodegradation	ready biodegradable	Not ready biodegradable	ready biodegradable	Not ready biodegradable
Acute Oral Toxicity	IV	III	IV	III

Table 3 summarizes the ADME/T test findings for specific ligand compounds. They are all highly absorbed by human intestinal tissue and have the ability to pass the blood-brain barrier ^{30, 31, 32} . There was no P-glycoprotein inhibitory action demonstrated by any of the ligand compounds ³³. The Caco2 cell line can withstand all of the chosen chemicals. P-coumarin is a strong inhibitor of CYP450 1A2, but caffeine and ferulic acid showed no inhibitory impact on the cytochrome P450 family of proteins. P-coumarin and diferulic acid are not easily biodegradable, whereas caffeineic and ferrulic acids are. The carcinogenicity and AMES toxicity of both molecules were ³⁴.

DISCUSSION:

Plants are valuable source of secondary metabolites with important therapeutic value in curing disease. In vitro, studies using different plant extracts have already been shown to process thrombolytic activity³⁵. In our current study, four phenolic compounds are selected and were docked with their target proteins (tPA). Our molecular docking study suggested that all ligand molecules exhibit thrombolytic activity but the lowest binding energy ligand shown most favourable interactions and highest affinity binding (-9.17757 kcal/mol), which occupies number of residues within the target protein binding site³⁶.

Specific chemical characteristics of compounds that are thought to be essential to lead discovery are called drug-likeness features. The Lipinski rule of five aids in identifying chemical characteristics that affect medication bioavailability and membrane permeability in biological systems, among other attributes. The absorption decreases as the log p increases. The candidate molecule's solubility is influenced by the log value, and the therapeutic molecule under investigation is always better off with the lowest value. Every ligand molecule in this experiment complied with Lipinski's rule of five. The molecule with the lowest binding energy (-9.17757 kcal/mol) was found to be caffeic acid.

The greatest effects have been observed in caffeic acid's narcotic characteristics. Its log p value is 0.97, log s value is -1.89, and its molecular weight is 180.16g/mol. Caffeic acid's hydrogen bond acceptor is (4), while its hydrogen donor is (3). Caffeic acid has two rotatable bonds, thirteen heavy atoms, and a molecular inflection at (47,16). We discovered a drug score of 0.86 and a drug similarity score of (0.56). Prior to lead identification, in-silico ADME/T testing offers hints regarding important pharmacokinetic and pharmacodynamic features of compounds, saving money and time by lowering failure rates in late stage discovery methodologies. Diminish. When a medication predominantly targets brain cells, the blood-brain barrier's permeability becomes significant. The blood-brain barrier can be crossed by caffeineic acid. The metabolism, excretion, and interactions of drugs are significantly influenced by cytochrome P450 enzymes in the body. Table 3 displays the inhibitory effect of caffeine on CYP450 1A2. When all factors were taken into account, caffeine outperformed all other ligand molecules in this experiment in ADME/T.

Finally, Caffeic acid performed exceptionally better than the other ligand molecules in all tests in this study, making caffeic acid the natural thrombolytic agent of choice over the above ligand molecules. The goal behind selecting the plant derived compounds is they lack side effects, easily available, in expensive, can be used as home remedies. A combination of these compounds would ensure that the patients do not reach a critical condition^37,38.

CONCLUSION:

Finally it can be concluded that based on results of molecular docking, ADME/T tests and Drug likeliness characteristics, Caffeic acid can be a good source of thrombolytic drugs because current drugs have many disadvantages such as bleeding and other complications. Further In -vivo studies are required to explore potential thrombolytic activity of caffeic acid.

ACKNOWLEDGE:

We are grateful to members of the Department of Pharmacology, for their support in accomplishing the work. Also, we are extremely thankful to Dr. Y. Srinivas, Principal of Vignan institute of Pharmaceutical technology.

CONFLICT OF INTEREST:

There are no conflicts of interest.

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Received on 27.09.2023      Revised on 17.04.2024

Accepted on 27.09.2024   Published on 28.01.2025

Available online from February 27, 2025

Research J. Pharmacy and Technology. 2025;18(2):563-570.

DOI: 10.52711/0974-360X.2025.00084

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