Implementation of computational methods for designing potential inhibitors against human p38α protein

Abstract p38α, a non-receptor serine/threonine kinase, plays an essential role in cell proliferation, cell differentiation, apoptosis, production of cytokines such as IL1β and TNFα, senescence and tumorigenesis. Over expression of p38α enhances the production of cytokines, leading to inflammation causing cancers. Therefore, the protein p38α is selected as a target for the inhibition of progression of inflammatory cancers. SB203580, BIRB796, 2H-quinolizine-2-one, 7-alkyl-1,5-bis–aryl-pyrazolo pyridinones, aML3403, N-pyrimidyl amides, Fused pyrazoles, SD0006, 4-3-(4-fluoro phenyl )-1H-pyrazol-4-yl)pyridine are the nine published inhibitors for the p38α, but they show side effects like liver toxicity and the development of lung tumors, particularly in smokers, some of which are in the preclinical stage. A small molecule library of 3495 structural analogs of the nine published inhibitors was prepared for ligand based virtual screening. Multiple conformations of the ligands were generated and conformations with ADME violations were discarded. The optimized ligand conformations were docked flexibly into the active site of optimized p38α crystal structure. Fourteen lead molecules obtained were ranked based on XP G-score and binding orientation. In comparison with the nine existing inhibitors, lead ‘1’ (N-(3-Benzooxazol-2-yl-4-hydroxy-phenyl) 2ptolyloxyacetamide) had the highest binding affinity among the lead molecules with XP Gscore of -9.38 kcal/mol and formed four hydrogen bonds: one with each of Ala 51, Glu71 and Asp168 and one water bond (position 420) with binding mode which complements well the crystallographic data of human p38α. The docking result shows the potency of lead ‘1’ as a promising inhibitor for regulating the activity of p38α.