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

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-beta-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 q(2) value of 0.605, r(n)(cv)(2) value of 0.958 and r(pred)(2) value of 0.553. Optimized CoM-SIA analysis (SEHD) showed q(2) value of 0.580, r(pred)(2) value of 0.953 and r(pred )(2)value of 0.723. Topomer CoMFA analysis showed q(2) value of 0.684, r(2) (conventional correlation coefficient) value of 0.955 and r(pred)(2) value of 0.721. HQSAR analysis showed q(2), r(2) and r(pred)(2) 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. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

This study carried out 3D-QSAR research on Tankyrase inhibitors using various techniques, providing significant insights for the design of novel quinazolinone derivatives as potent inhibitors.