Rational design of promiscuous binding modulators of p53 inducing E3(Ub)-ligases (Mdm2 and Pirh2) as anticancer agents: an in silico approach

摘要: In this study, for the first time, we report on in silico based development of Mdm2 and Pirh2 promiscuous binding small molecule modulators. The methodology involves capturing important interacting residues p53 TAD TET, respectively from literature; as well protein–protein docking molecular dynamics simulations applied present study. knowledge that have been already delineated was used benchmark design focused ligand libraries, which were obtained by pharmacophore screening 3.9 million compounds deposited MMsINC® database. This followed 2D fingerprint similarity filtering libraries with respect to a known reference set inhibitors, further confined chemical space 608 molecules. These included 365 Mdm2-like mimetics 243 TET. Docking iterations respective targets reverse resulted twelve potential best fit molecules showed favourable interactions both pBD CTD. quality protocol assessed using experimentally determined IC50 values 213 inhibitors their scores statistical measures, good correlations.