Combined structure-based pharmacophore, virtual screening, and 3D-QSAR studies of structural diverse dehydrosqualene synthase inhibitors

Dehydrosqualene synthase (CrtM) is a key enzyme in the synthesis of presqualene diphosphate in Staphylococcus aureus. In the current study, a combination of structure-based pharmacophore and 3D-QSAR methods are used to clarify the essential quantitative structure–activity relationship (QSAR) of known CrtM inhibitors; the multicomplex-based pharmacophore (MCBP) guided method has been suggested to generate a comprehensive pharmacophore of CrtM based on twenty crystal structures of CrtM inhibitor complex. Performances of the MCBP-based virtual screening approach were applied to screen specs chemical databases (202, 408 compounds). Thirty-eight compounds were selected from the final hits and should be shifted to experimental studies. The MCBP model has been successfully used to identify the bioactive conformation and align 24 structurally diverse CrtM inhibitors. The QSAR analyses have been performed on these CrtM inhibitors based on MCBP guided alignment. These results may provide important information for further design and discovery of novel CrtM inhibitors.