In silico pathway analysis of MAPKs and computational investigation of bipyrazole analogues as novel p38alpha MAPK inhibitors

Abstract

Mitogen-Activated Protein Kinase MAPK belongs to one of the largest super-families of proteins. The activity of most MAPKs is stimulated by a large variety of signals, including mitogens, growth factors, cytokines, T-cell antigens, pheromones, UV and ionising radiations, osmotic stress, heat shock, oxidative stress and others. The present work determines the participation of particular MAPK to one specific pathway in the MAPKinase signalling MAPK 1-14. Various computational analyses involving Clustal omega, phylogenetic tree reconstruction and ProDom have been utilised in the study. Based on evolutionary relationships, domain detections and comparison of active site residues, the specificity of MAPKs in defined pathways is emphasised. MAPKs have been shown to play a pivotal role in diverse diseases, including cancer. Majority of studies have focused on targeting p38 MAPK isoform alpha MAPK14. Hence, in this paper we elucidate a computational mechanism of inhibition by bipyrazole analogues, for the first time, as promising inhibitors of p38alpha MAPK.