3D-QSAR modeling of Phosphodiesterase-5 inhibitors: evaluation and comparison of the receptor- and ligand-based alignments
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Phosphodiesterase-5 (PDE5) inhibitors can be used as clinical agents for the treatment of erectile dysfunction and pulmonary hypertension. A series of aryl-chromeno-pyrrol derivatives were previously identified as PDE5 inhibitors in our lab. Herein, these molecules were subjected to 3D-QSAR analysis with CoMFA and CoMSIA methods to gain deeper insight into the structural requirements for their bioactivities. Receptor- and ligand-based alignment were used and compared to find the alignment-related factors that affect the accuracy of QSAR models. The receptor-based CoMFA and CoMSIA models, which were generated by superimposing the docking conformations directly in the protein binding site, gave more significant results for 38 training set compounds and 5 test set molecules. Comparison of the two alignments revealed that spatial arrangement of the ligands is the principal factor in determining the reliability of the 3D-QSAR models. Detailed analysis of the receptor-based CoMSIA-SE contour maps provided much helpful information to improve the bioactivities of aryl-chromeno-pyrrol analogs as PDE5 inhibitors.
Keywords:Phosphodiesterase PDE5 inhibitor 3D-QSAR CoMFA CoMSIA
This work was supported by the Natural Science Foundation of China (81602968); the Natural Science Foundation of Guangdong Province (2016A030313589); the Medical Scientific Research Foundation of Guangdong Province (A2016201); and Science and Technology Program of Guangzhou, China (201707010049); Guangdong provincial Project (2016A020226018).
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Conflict of interest
The authors declare that they have no conflict of interest.
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