The first report on predictive comparative ligand-based multi-QSAR modeling analysis of 4-pyrimidinone and 2-pyridinone based APJ inhibitors

Abstract

The apelin–apelin receptor (APJ) system has been a promising biomolecular target participating crucially in several major disorders including cardiovascular diseases, neurodegenerative diseases, metabolic disorders, and lung, liver, and kidney-related diseases as well as in cancer. Though it is a promising therapeutic target for drug design for such diverse disease conditions, surprisingly no such molecular modeling study has been performed to date. This study reports the first predictive comparative multi-QSAR modeling analysis (like stepwise linear regression QSAR, MIA-QSAR, 3D-QSAR CoMFA, and CoMSIA) on a series of 4-pyrimidinone and 2-pyridinone-based APJ inhibitors to assimilate the knowledge regarding the crucial structural and physicochemical features responsible for the modulation of the APJ inhibitory effects. The statistically validated multi-QSAR modeling study unveils the importance of several crucial structural features responsible for modulating APJ inhibition. The presence of the 5-benzyl-1,3,4-oxadiazole ring, the higher number of hydrogen bond acceptor groups, and 4-chlorobenzyl, 4-bromobenzyl, and 2-methoxy groups may favor APJ inhibitory effects. However, bulky thiophenyl and n-butyl groups are detrimental to APJ inhibition. This current study may accelerate the process of the design and discovery of novel and highly potential APJ inhibitors for the effective treatment of multiple life-threatening disease conditions.