3D-QSAR analysis of cycloguanil derivatives as inhibitors of A16V + S108T mutant Plasmodium falciparum dihydrofolate reductase enzyme

A three-dimensional quantitative structure–activity relationship (3D-QSAR) study was carried out on cycloguanil derivatives which are reported as growth inhibitors of Plasmodium falciparum clone (T9/94 RC17) which harbors A16V + S108T mutant dihydrofolate reductase (DHFR) enzyme. Comparative of Molecular Field Analysis (CoMFA) and Comparative of Molecular Similarity Indices Analysis (CoMSIA) were carried out to investigate the structural requirements for the activities of these compounds and to derive predictive models that may be used for designing novel PfDHFR enzyme inhibitors. The global minimum energy (within the search space) conformation of the most active compound (38) was obtained by using simulated annealing, and was subsequently used as a template to build the structures of the rest molecules used in the study. The CoMFA model gave statistically significant results with rcv2 and rncv2 values of 0.654 and 0.951, respectively. The combination of steric, electrostatic and hydrophobic fields resulted in the best CoMSIA model with rcv2 and rncv2 values of 0.669 and 0.907, respectively. The predictive abilities of the CoMFA and CoMSIA models were also evaluated using test compounds which gave rpred2 values of 0.735 and 0.557, respectively. The results of bootstrapping analyses also confirmed that the generated models are robust and reliable. The models were graphically interpreted using CoMFA and CoMSIA contour plots. The structural regions responsible for the differences in anti-plasmodial activities were analyzed with respect to their electrostatic, steric and hydrophobic nature. The results obtained from this study could be used for rational design of potent inhibitors against A16V + S108T mutant PfDHFR enzyme.