Design of new CD38 inhibitors based on CoMFA modelling and molecular docking analysis of 4‑amino-8-quinoline carboxamides and 2,4-diamino-8-quinazoline carboxamides

ABSTRACT

In this study, based on molecular docking analysis and comparative molecular field analysis (CoMFA) modelling of a series of 71 CD38 inhibitors including 4‑amino-8-quinoline carboxamides and 2,4-diamino-8-quinazoline carboxamides, new CD38 inhibitors were designed. The interactions of the molecules with the greatest and the lowest activities with the nicotinamide mononucleotide (NMN) binding site were investigated by molecular docking analysis. A CoMFA model with four partial least squares regression (PLSR) components was developed to predict the CD38 inhibitory activity of the molecules. The r² values for the training and test sets were 0.89 and 0.82, respectively. The Q² values for leave-one-out cross-validation (LOO-CV) and leave-many-out cross-validation (LMO-CV) tests on the training set were 0.65 and 0.64, respectively. The CoMFA model was validated by calculating several statistical parameters. CoMFA contour maps were interpreted, and structural features that influence the CD38 inhibitory activity of molecules were determined. Finally, seven new CD38 inhibitors with greater activity with respect to the greatest active molecules were designed.

KEYWORDS:

• CD38 inhibitors
• CoMFA
• molecular docking
• 4‑amino-8-quinoline carboxamides
• 2-diamino-8-quinazoline carboxamides

Supplemental Material

Supplementary material for this article can be accessed at: https://doi.org/10.1080/1062936X.2018.1545695

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.