In silico screening of some phytochemicals for antiplatelet drug targets

Cardiovascular diseases (CVDs) are the leading cause of death globally, with an estimated 17.9 million deaths each year, a number that is predicted to increase more than 23.6 million by 2030.There are many antiplatelet drugs which are being used for a long time to treat and prevent of CVDs. All of these drugs are accompanied by a diversity of adverse effects such as drug resistance, high bleeding risk and gastrointestinal toxicity. Thus researchers are seek for new antiplatelet agents with fewer or no side effects and better efficacy. Ruta graveolens, Hypericum Perforatum, Magnolia Obovata, etc., which are known to be used in the treatment of CVDs in traditional medicine. Although there are human and animal experiments of some phytochemicals (dictamin, rutin, magnolol, etc.) of these plants, there is no theoretical study including their binding energies and properties to platelet receptors. In this thesis, the inhibitory potential and antiplatelet properties of these phytochemicals on platelet function will be examined against 5 antiplatelet targets (COX-1, P2Y12, GP-VI, PDE-3, and PAR-1) using molecular modeling methods. Their interaction modes will be explained, and an evaluation will be made about potential drug candidates by calculating computational biological activity values. Firstly to confirm the accuracy of docking simulation process, a redocking approach was performed using the coded structures 3N8X, 4NTJ, 1SO2, and 3VW7. All RMSD values were less than 2 Å and this confirmed the reliability of molecular docking parameters and algorithms. In the second part Compounds were docked to each of five antiplatelet targets, to calculate their binding affinity. In the third step, Top five compounds with good binding energies viz., graveolinine against cox-1, sanguinarine against P2Y12 and PDE3, rutin against collagen and bisdemethoxycurcumin against PAR-1 were considered for molecular dynamic simulations. The simulated complexes confirmed the binding stability between the ligands and the proteins. In the fourth step, Binding stability between simulated ligands and proteins was confirmed by molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) binding analysis. The MM-PBSA analysis results indicated that in all docked complexs the major contributors of binding were van der Waals interactions. The polar solvation energy did not contribute to their binding energy due to its positive value, while the rest of the components viz van der Waals energy, non-polar solvation energy, and electrostatic interaction energy with negative value made a significant contribution in interaction energy and stability of system. The binding energy decomposition analysis revealed per residue contribution for each complex. In the last part of the study, In order to check the efficacy and bioavailability of compounds, swissADME and ADMETlab servers were used to evaluate the drug-likeness, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of them. As a result, The data obtained from this study will contribute to new antiplatelet drug design studies.