Free energy perturbation (FEP)-guided scaffold hopping

Abstract 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 greater advantages to precisely predict the theoretical binding potencies ΔGFEP between ligands and their target, which were more consistent with the experimental binding potencies ΔGEXP (the mean absolute deviations ⎢ΔGFEP‒ΔGEXP⎢