Computer-aided molecular design of new potential inhibitors of protein kinases using of 4-methyl-benzoic acid as a linker
Aliaksandr Faryna, Еlena N. Kalinichenko · SDRP Journal of Computational Chemistry & Molecular Modelling · 2019
Considering pharmacophore features of known protein kinase inhibitors, we created virtual library of new 4-methylbenzamide derivatives.Docking of target structures was performed using nine cancerrelated protein kinases as receptors.Docking protocol was validated using approved kinase inhibitors.Protein-ligand complexes with the best score were treated by visual inspection and the structure 7 containing benzimidazole k for ATP-site and fragment of 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline f was considered as the most promising substance.Based on docking results, the most favorable structures were evaluated via molecular dynamics with MM/PBSA free binding energy calculation showing in some cases comparable with known inhibitors results in terms of total binding energy, polar and non-polar interactions with best result -160.0 kJ/mol for T315I-mutant ABL kinase.Mean binding energy for approved kinase inhibitors was -161.0 kJ/mol.It was shown, that directed structural modifications of initial structures could further increase calculated binding energy.The combined docking and molecular dynamics results suggest that proposed structures could be valuable objects in the development of new kinase inhibitors with the derivatives of 4-[(1H-1,3,-benzodiazole-2yl)methyl]-N-phenylbenzamide being most promising ones having docking score of -12.6 and binding energy of -157.6 kJ/mol in the respect of human ABL kinase.