Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds,which is a topic of high interest in organic and medicinal ch...Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds,which is a topic of high interest in organic and medicinal chemistry.However,most approaches cannot efficiently predict the potency level of candidates after scaffold hopping.Herein,we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation(FEP)-guided scaffold-hopping strategy,and FEP shows great advantages to precisely predict the theoretical binding potenciesΔGFEPbetween ligands and their target,which were more consistent with the experimental binding potenciesΔGEXP(the mean absolute deviations|ΔGFEP-ΔGEXP|<2 kcal/mol)than thoseΔGMM-PBSAorΔGMM-GBSApredicted by the MM-PBSA or MM-GBSA method.Lead L12 had an IC_(50) of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil.Our work provides the first report via the FEPguided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold,implying that it will have a variety of future applications in rational molecular design and drug discovery.展开更多
基金supported by Natural Science Foundation of China(21877134,81872727,22077143,21702238,82003576,and 81703341)Guangzhou Science and Technology Project(The People’s Livelihood Programs for Science and Technology,201803010075,China)+1 种基金Science Foundation of Guangzhou City(201904020023,China)Fundamental Research Funds for Hainan University(KYQD(ZR)-21031,China)。
文摘Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds,which is a topic of high interest in organic and medicinal chemistry.However,most approaches cannot efficiently predict the potency level of candidates after scaffold hopping.Herein,we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation(FEP)-guided scaffold-hopping strategy,and FEP shows great advantages to precisely predict the theoretical binding potenciesΔGFEPbetween ligands and their target,which were more consistent with the experimental binding potenciesΔGEXP(the mean absolute deviations|ΔGFEP-ΔGEXP|<2 kcal/mol)than thoseΔGMM-PBSAorΔGMM-GBSApredicted by the MM-PBSA or MM-GBSA method.Lead L12 had an IC_(50) of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil.Our work provides the first report via the FEPguided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold,implying that it will have a variety of future applications in rational molecular design and drug discovery.
