QSAR studies on the human sirtuin 2 inhibition by non-covalent 7,5,2-anilinobenzamide derivatives

Abstract

Sirtuin 2 is a key enzyme in gene expression regulation that is often associated with tumor proliferation control and therefore is a relevant anticancer drug target. Anilinobenzamide derivatives have been discussed as selective sirtuin 2 inhibitors and can be developed further. In the present study, hologram and three-dimensional quantitative structure–activity relationship (HQSAR and 3D-QSAR) analyses were employed for determining structural contributions of a compound series containing human sirtuin-2-selective inhibitors that were then correlated with structural data from the literature. The final QSAR models were robust and predictive according to statistical validation (q² and r²_pred values higher than 0.85 and 0.75, respectively) and could be employed further to generate fragment contribution and contour maps. 3D-QSAR models together with information about the chemical properties of sirtuin 2 inhibitors can be useful for designing novel bioactive ligands.

Communicated by Ramaswamy H. Sarma

Keywords:

• Anilinobenzamide
• CoMFA
• CoMSIA
• epigenetic
• HQSAR
• sirtuin

Acknowledgments

The authors thank OpenEye Scientific Software for ROCS, OMEGA and QUACPAC academic licenses.

Author contribution

GMF, TK and VGM contributed to the experiment design. GMF, JGM, TK and VGM contributed to dataset organization. GMF and VGM contributed to model inference and validation. TK, GHT, AG, FSE and VGM contributed to discussion and writing of the paper.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the CNPq [grant number 312009/2014-3], [grant number 456984/2014-3], [grant number 310232/2017-1], [grant number436791/2018-8]; FAPESP [grant number 2017/25543-8]; GlaxoSmithKline; and CAPES.