MM-PBSA and per-residue decomposition energy studies on 7-Phenyl-imidazoquinolin-4(5H)-one derivatives: Identification of crucial site points at microsomal prostaglandin E synthase-1 (mPGES-1) active site

Abstract

The huge therapeutic potential and the market share of painkillers are well-known. Due to the side effects associated with traditional NSAIDs and selective cyclooxygenase (COX-2) inhibitors, a new generation of painkillers is the need of the hour. In this regard, microsomal prostaglandin E synthase-1 (mPGES-1) offers great potential as an alternative drug target against inflammatory disorders. The present study is aimed at identifying the amino acids crucial in effective inhibitor binding at the mPGES-1 active site by performing molecular dynamics based studies on a series of 7-Phenyl-imidazoquinolin-4(5H)-one derivatives. Molecular dynamics (MD) simulations, MM-PBSA, per-residue energy decomposition and Dimensionality Reduction through Covariance matrix Transformation for Identification of Differences in dynamics (DIRECT-ID) analysis were performed to get insights into the structural details that can aid in novel drug design against mPGES-1. The high correlations of electrostatic and polar energy terms with biological activity highlight their importance and applicability in in silico screening studies. Further, per-residue energy decomposition studies revealed that Lys42, Arg52, Arg122, Pro124, Ser127, Val128 and Thr131 were contributing more towards inhibitor binding energy. The results clearly show that MM-PBSA can act as a filter in virtual screening experiments and can play major role in facilitating various mPGES-1 drug discovery studies.