Free energy perturbation (FEP)-guided scaffold hopping

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 potencies Delta G(FEP) between ligands and their target, which were more consistent with the experimental binding potencies Delta G(EXP) (the mean absolute deviations vertical bar Delta G(FEP) - Delta G(EXP)vertical bar < 2 kcal/mol) than those GMM-PBSA or Delta G(MM-PBSA) predicted by the Delta G(MM-GBSA) or MM-GBSA method. Lead L12 had an IC50 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 FEP- guided 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. (C) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

Automated summary

This study employed a free energy perturbation (FEP)-guided scaffold-hopping strategy to identify potent PDE5 inhibitors with a novel scaffold. The FEP approach showed advantages in accurately predicting binding potencies, and the discovered lead compound exhibited a different binding pattern compared to a famous starting drug. The findings highlight the potential of the FEP-guided scaffold hopping strategy in rational molecular design and drug discovery.