Molecular Docking of Ferulic Acid Derivatives on P2Y12 Receptor and their ADMET Prediction
Keywords:ADMET prediction, antiplatelet, ferulic acid, molecular docking, P2Y12 receptor.
P2Y12 is a platelet receptor that is involved in ADP signal transduction and is an attractive target for antithrombotic drugs. The side effects of antithrombotic drugs are not pleasant for the patient, so research into the development of new antithrombotic agents is still necessary. Evaluation of absorption, distribution, metabolism, elimination, and the toxicity profile of candidate drugs is an important step in drug development. The aim of this study was to predict the potency of ferulic acid (FA) and its derivatives (FA1-24) as antiplatelet drugs by a docking study on the P2Y12 receptor (PDB ID: 4PXZ) and their ADMET performance. The docking study was performed using Molegro Virtual Docker, version 5.5. ADMET prediction of FA was conducted using the pkCSM online tool. The results of the in silico study showed that FA-19 had the lowest MolDock score (MDS), which means that this compound is predicted to have the greatest activity. FA-19 is also predicted to be practically non-toxic. It is expected that FA-19 will have good intestinal absorption and is similarly distributed in the intestine and in the blood plasma. Its penetration in the blood-brain barrier is moderate but does not inhibit the CYP2D6 and CYP3A4 enzymes.
Agency of Research and Development, Research of Basic Health 2013, Ministry of Health Republic Indonesia, pp. 1-384, 2013. http://www.depkes.go.id/resources/download/general/Hasil/Riskesdas/ 2013.pdf, (10 April 2017). (Text in Indonesian)
Ahn, Y.A, Lee, J-Y., Park H.D., Kim, T.H., Park, M.C., Choi, G. & Kim S., Identification of a New Morpholine Scaffold as a P2Y12 Receptor Antagonist, Molecules, 21(9), pp. 1114, 2016. DOI:10.3390/molecules 21091114
North, R.A. & Jarvis, M.F., P2X receptors as Drug Targets, Mol. Pharmacol., 83(4), pp. 759-769, 2013. DOI:10.1124/mol.112.083758
Cattaneo, M., Advances in Antiplatelet Therapy: Overview of New P2Y12 Receptor Antagonists in Development, Eur. Hear. J. Suppl., 10(Suppl I), pp. I33-I37, 2008. DOI:10.1093/eurheartj/sun037
Paoletta, S., Sabbadin, D., Kugelgen, I. von, Hinz, S., Katritch, V., Hoffmann, K., Abdelrahman, A., Strabburger, J., Baqi, Y., Zhao, Q., Stevens, R.C., Moro, S., Muller, C.E., Jacobson, K.A., Modelling Ligand Recognition at P2Y12 Receptor in Ligth of X-Ray Structural Information, J Comput Aided Mol Des, 29(8), pp. 737-756, 2015. DOI:10.1007/s10822-015-9858-z
Dudley, A., Thomason, J., Fritz, S., Grady, J., Stokes, J., Wills, R., Pinchuk, L., Mackin, A. & Lunsford, K., Cyclooxygenase Expression and Platelet Function in Healthy Dogs Receiving Low-Dose Aspirin, J. Vet. Intern. Med., 27(1), pp. 141-149, 2013. DOI:10.1111/jvim.12022
Kumalo, H.M., Bhakat, S. & Soliman, M.E., Theory and Applications of Covalent Docking in Drug Discovery: Merits and Pitfalls, Molecules, 20(2), pp. 1984-2000, 2015. DOI:10.3390/molecules20021984
Chelucci, R.C., Dutra, L.A., Lopes Pires, M.E., de Melo, T.R., Bosquesi, P.L., Chung, M.C. & Dos Santos, J.L., Antiplatelet and Antithrombotic Activities of Non-steroidal Anti-inflammatory Drugs Containing an n-Acyl Hydrazone Subunit, Molecules, 19(2), pp. 2089-2099, 2014. DOI:10.3390/molecules19022089
Zhang, P-X., Lin, H., Qu, C., Tang, Y-P., Li, N-G., Kai, J. Shang, G., Li, B., Zhang, L. Yan, H., Liu, P. & Jin-Ao Duan, J-A., Design, Synthesis, and In Vitro Antiplatelet Aggregation Activities of Ferulic Acid Derivatives, J. Chem., 2015(Art.ID. 376527), pp. 1-7, 2015. DOI:10.1155/2015/376527
Yang, X.Z., Diao, X.J., Yang, W.H., Li, F., He, G.W., Gong, G.Q. & Xu, Y.G., Design, Synthesis and Antithrombotic Evaluation of Novel Dabigatran Prodrugs containing Methyl Ferulate, Bioorganic Med. Chem. Lett., 23(7), pp. 2089-2092, 2013. DOI:10.1016/j.bmcl.2013.01. 126
Li, J., Zhou, N., Luo, K., Zhang, W., Li, X., Wu, C. & Bao, J., In Silico Discovery of Potential VEGFR-2 Inhibitors from Natural Derivatives for Anti-angiogenesis Therapy, Int. J. Mol. Sci., 15(9), pp. 15994-16011, 2014. DOI:10.3390/ijms150915994
Somer Jr., F.L., Molecular Modelling for Beginners (Alan Hinchliffe), J. Chem. Educ., 81(11), pp. 1573, 2004. DOI:10.1021/ed081p1573
Tsaioun, K., Blaauboer, B.J. & Hartung, T., Evidence-based Absorption, Distribution, Metabolism, Excretion (ADME) and its Interplay with Alternative Toxicity Methods, ALTEX, 33(4), pp. 343-358, 2016. DOI:10.14573/altex.1610101
Moroy, G., Martiny, V.Y., Vayer, P., Villoutreix, B.O. & Miteva, M.A., Toward in Silico Structure-based ADMET Prediction in Drug Discovery, Drug Discov. Today, 17(1-2), pp. 44-55, 2012. DOI: 10.1016/j.drudis. 2011.10.023
Rutgers and UCSD/SDSC, 4PXZ Crystal Structure in Complex with 2MeSADP, RCSB Protein Data Bank, http://www.rcsb.org/structure/ 4pxz, (12 December 2016). DOI: 10.2210/pdb4PXZ/pdb
National Cancer Institute, Online SMILES Translator, United States https://cactus.nci.nih.gov/translate/, (20 June 2017).
Pires, D.E.V., Blundell, T.L. & Ascher, D.B., The University of Melbourne's pkCSM Small-molecule Pharmacokinetics Prediction, http://biosig.unimelb.edu.au/pkcsm/ prediction/, (20 June 2017).
Charite University of Medicine-Institute for Physiology, ProTox-II - Prediction Of Toxicity Of Chemicals, http://tox.charite.de/protox_II/ (20 June 2017).
Kaushik, P., Lal Khokra, S., Rana, A.C. & Kaushik, D., Pharmacophore Modeling and Molecular Docking Studies on Pinus roxburghii as a Target for Diabetes Mellitus, Adv. Bioinformatics, 2014(Art.ID. 903246), 2014. DOI:10.1155/2014/903246
Lipinski, C.A., Lombardo, F., Dominy, B.W. & Feeney, P.J., Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings, Adv. Drug Deliv. Rev., 23(1-3), pp. 3-26, 1997.
Pires, D.E., Blundell, T.L. & Ascher, D.B., pkCSM: Predicting Small-molecule Pharmacokinetic and Toxicity Properties using Graph-based Signatures, J. Med. Chem., 58(9) pp. 4066-4072, 2015. DOI:10.1021/ acs.jmedchem.5b00104