Structural insights on 2-phenylquinazolin-4-one derivatives as tankyrase inhibitors through CoMFA, CoMSIA, topomer CoMFA and HQSAR studies

Abstract Tankyrase is an emerging target of 17 membered poly(ADP-ribose)polymerase enzyme family for the treatment of Wnt driven cancers. TNKS are associated with many cellular functions; Wnt–β-catenin signaling, telomere homeostasis, mitotic spindle formation etc. The inhibition of cell growth could be achieved by the inhibition of TNKS through Wnt-signaling mechanism. To develop novel lead molecules as tankyrase inhibitors, we performed 3D-QSAR studies on 37 reported 2-phenylquinazolin-4-one derivatives. Training set contained 29 while test set contained 8 molecules. Four different techniques, CoMFA, CoMSIA, Topomer CoMFA and HQSAR were used to generate the QSAR models. Distill alignment based CoMFA analysis showed q2 value of 0.605, r2ncv value of 0.958 and r2pred value of 0.553. Optimized CoMSIA analysis (SEHD) showed q2 value of 0.580, r2ncv value of 0.953 and r2pred value of 0.723. Topomer CoMFA analysis showed q2 value of 0.684, r2 (conventional correlation coefficient) value of 0.955 and r2pred value of 0.721. HQSAR analysis showed q2, r2 and r2pred values of 0.833, 0.951 and 0.753, respectively. Combined results of all studies provided significant output in terms of substitutions required for activity and can be used for the design of novel quinazolinone derivatives as potent tankyrase inhibitors.