Investigation of structure–activity relationship: In silico studies of [1, 2, 4]triazolo[4, 3-a]pyridine ureas as P38 kinase inhibitors

Abstract

P38 kinases are the members of serine/threonine kinases family and play a vital role in the progression of inflammation. In the past two decades, numerous p38 kinase inhibitors have been reported, and few of them have failed in clinical trials. Recently, some of the p38 kinase inhibitors have entered in clinical trials for the treatment of Alzheimer’s disease. A potential opportunity exists for medicinal chemistry for the discovery of potent and safe p38 kinase inhibitors. In view of this challenging opportunity, the present manuscript is aimed towards development of a 3D quantitative structure–activity relationship (QSAR) model and the docking and dynamic simulation studies. A statistically robust 3D QSAR model was developed by employing 21 training set molecules which is attributed with appreciating cross-validation coefficient (q2) of 0.0.6269 and conventional correlation coefficient (r2) of 0.8783 respectively. The predicted correlation coefficient (r2 pred) was found to be 0.8644 and standard error of 0.3331. The molecular docking analysis of all the p38 kinase inhibitors revealed that the analogs were well docked into the DFG (Asp-Phe-Gly motif) out pocket of p38 kinase and exhibited hydrogen bond interactions with Asp186 and Lys71. Extension of docking studies to the molecular dynamics simulation study informed that the ligand displayed the strong conformational stability within the active site of p38 kinase forming maximum two hydrogen bonds until 100 ns respectively.