Molecular docking and virtual screening studies of potential protein kinase inhibitors

Abstract

The purpose of the study was to study in detail the molecular docking in a detailed way and also to do the computational studies related to different glide docking simulations and quantitative studies of structural activity relationship. For that purpose, different successful methodical results were attained by using different methods of the docking simulations. First of all, docking simulation was done for one of a 3-carboxamido-2H-indazole-6-arylamide derivative which was potent and selective CRaf inhibitor by using glide XP docking (extra precision) method. It was observed that one of the 3-carboxamido-2H-indazole-6-arylamide derivatives was showing potency and selectivity CRaf kinase over BRaf. For molecular docking studies of 4-arylamido 3-methyl isoxazole derivative as a novel FMS kinase inhibitor, induced fit docking was used for docking simulation and rescued false negative result of the compound with the protein kinase. The docking studies showed that one of the potent derivatives, 4-arylamido 3-methyl isoxazole was well bound to the active site of FMS kinase. For Aurora A kinase inhibition through molecular docking studies, SP (standard precision) was used as a rational work flow for glide docking was used and it showed that 1,2,3-triazolylsalicylamides which was potent against Aurora A kinase was nicely bound and the study showed that addition of phenolic group to the salicylamide scaffold was showing a key hydrogen bonding interaction with the receptor resulting in a significant increase of the activity and our compound was also quite nicely aligned with the co-crystal structure of Aurora A (SNS-314). CRaf and BRaf V600E under Raf kinases are involved in considerable amount of melanomas. For that purpose we studied the molecular docking studies of the pyrimidine-4-yl-1H-imidazole-2-yl derivatives which were quite potent against BRaf V600E and CRaf and from the docking simulation it showed that addition of the carbonyl/methylene moieties could enhance the selectivity and potency of Raf kinases if they are added to imidazole derivative. To identify the hit compounds, HTVS (high throughput virtual screening) was done for about 0.5 millions of compounds from the Asinex Chemical Library and on the basis of docking score, hydrogen bond dimensions strength and energy terms, it showed that few of the compounds from the library were showing good binding interactions at the active site along with docking score in energy terms and they were considered as hit on the basis of ligand binding energy which comes from the empirical scoring function, called glide score including electrostatic and van der Waals interactions. Addition to the molecular docking studies, 3D-QSAR studies were carried out for the JNK2 kinase inhibitor derivatives. Aligning and CoMFA studies were done to describe the steric favored and disfavored for the molecules along with the electrostatic distribution to find out that how should we increase further the selectivity and potency of different derivatives for JNK2.