Molecular modeling studies on 3,4-dihydroquinazolines as trypanothione reductase inhibitors using 3D-QSAR and docking approaches

Abstract

The trypanothione reductase (TryR) has been used as a key validated target to guide drug discovery for human African trypanosomiasis (HAT). 3D-QSAR and docking studies were performed on a series of 3,4-dihydroquinazolines as TryR inhibitors to establish a molecular model for new drug design. The CoMFA and CoMSIA models resulted from 53 molecules gave r cv 2 values of 0.591 and 0.574, r 2 values of 0.968 and 0.943, respectively. The external validation indicated that CoMSIA model with a valid r m 2 value of 0.864 exhibited better predictive power than CoMFA model. 3D contour maps generated from CoMFA and CoMSIA along with the docking analyses have identified several key features responsible for the activity. A set of analogs were proposed by utilizing the results revealed in the present study, and were predicted with significantly improved potencies in the developed models. The results can be served as a useful guideline for designing novel 3,4-dihydroquinazoline derivatives with improved activity against human African trypanosomes.