Combined topomer CoMFA and hologram QSAR studies of a series of pyrrole derivatives as potential HIV fusion inhibitors

To have a better understanding of the relationship between structures and inhibitory activities of HIV fusion inhibitors, topomer comparative molecular field analysis (Topomer CoMFA) and hologram quantitative structure–activity relationship (HQSAR) were applied to study a series of pyrrole derivatives as potential HIV fusion inhibitors. Statistical results from the Topomer CoMFA model showed believable predictability based on the non-cross-validated value ( r 2 = 0.96), and the cross-validated value ( q 2 = 0.63). The r 2 and q 2 from the HQSAR model were 0.96 and 0.66, respectively, which also indicated the excellent predictability. External validations further proved the predictive potent of these two models with the r_pred^2 values of 0.96 for both the two models. Statistical results of the two models showed that they are all credible. In addition, we found a phenomenon that for some compound, bulky and negatively charged substitutions were favourable to its activity in the Topomer COMFA, but nitrogen contributed more positively than the bulkier and more negative chorine in the HQSAR. Therefore, in order to obtain more potential hits, the two models should be combined together. These studies would provide insights for the structure–activity relationship understanding of the small-molecule fusion inhibitors and be helpful for the rational design of novel fusion inhibitors in the future. Steric and electrostatics contour maps of compound A 1 were analysed to have a further study on structure necessities of pyrrole derivatives as HIV-1 fusion inhibitor.