7FAR

Crystal structure of PDE5A in complex with inhibitor L12

Summary for 7FAR

• Entry DOI: 10.2210/pdb7far/pdb
• Descriptor: cGMP-specific 3',5'-cyclic phosphodiesterase, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 40804.85

Authors

Wu, D.,Huang, Y.Y.,Luo, H.B. (deposition date: 2021-07-07, release date: 2022-05-18, Last modification date: 2023-11-29)

Primary citation

Wu, D.,Zheng, X.,Liu, R.,Li, Z.,Jiang, Z.,Zhou, Q.,Huang, Y.,Wu, X.N.,Zhang, C.,Huang, Y.Y.,Luo, H.B.
Free energy perturbation (FEP)-guided scaffold hopping.
Acta Pharm Sin B, 12:1351-1362, 2022

PubMed 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 a free energy perturbation (FEP)-guided scaffold-hopping strategy, and FEP shows great advantages to precisely predict the theoretical binding potencies Δ between ligands and their target, which were more consistent with the experimental binding potencies Δ (the mean absolute deviations  < 2 kcal/mol) than those Δ or Δ predicted by the MM-PBSA or MM-GBSA method. Lead had an IC 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 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.

PubMed: 35530128
DOI: 10.1016/j.apsb.2021.09.027

Experimental method

X-RAY DIFFRACTION (2.40006470991 Å)