HQSAR and topomer CoMFA for predicting melanocortin-4 receptor binding affinities of trans-4-(4-chlorophenyl) pyrrolidine-3-carboxamides

Abstract Hologram quantitative structure–activity relationships (HQSAR) and topomer comparative molecular field analysis (CoMFA) were implemented on a group of 73 trans-4-(4-chlorophenyl) pyrrolidine-3-carboxamides of piperazinecyclohexane compounds, and their binding affinities to the melanocortin-4 receptor (MC4R) were determined. The most effective HQSAR model was obtained using atoms and bonds as fragment distinction, and its cross-validated ( q 2 ) and non-cross-validated ( r 2 ) correlation coefficients were 0.665 and 0.907, respectively. Several external validation parameters (i.e., four ways to calculate the correlation coefficients of the test set samples), namely, Q F1 2 , Q F2 2 , Q F3 2 , and CCC , were 0.781, 0.766, 0.789, and 0.901, respectively. Topomer CoMFA models were built based on three fragment cutting modes. The most effective topomer CoMFA ( r 2  = 0.850, q 2  = 0.436, Q F1 2  = 0.784, Q F2 2  = 0.779, Q F3 2  = 0.751, and CCC  = 0.894) used the amide bond as the cut bond. Meanwhile, the predictive capabilities of the most effective HQSAR and topomer CoMFA models were tested and verified via an external test set with 15 compounds, and then compared with those of previously reported models. Molecular docking was employed to validate the results of the HQSAR and topomer CoMFA models. Moreover, the graphical results of HQSAR, topomer CoMFA, and docking were analyzed and used as guides in designing new MC4R ligands. The results of this work would be useful in chemical library design, virtual screening, and high-throughput screening.