Discovery of highly potent phosphodiesterase-1 inhibitors by a combined-structure free energy perturbation approach  

作　　者：Zhe Li Mei-Yan Jiang Runduo Liu Quan Wang Qian Zhou Yi-You Huang Yinuo Wu Chang-Guo Zhan Hai-Bin Luo 

机构地区：[1]State Key Laboratory of Anti-Infective Drug Discovery and Development,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China [2]Key Laboratory of Tropical Biological Resources of Ministry of Education,School of Pharmaceutical Sciences,Hainan University,Haikou 570228,China [3]Molecular Modeling and Biopharmaceutical Center and Department of Pharmaceutical Sciences,College of Pharmacy,University of Kentucky,Lexington,KY 40536,USA [4]Song Li’Academician Workstation of Hainan University(School of Pharmaceutical Sciences),Sanya 572000,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第12期5357-5369,共13页药学学报（英文版）

基　　金：supported by the National Key R&D Program of China(2023YFF1205102);National Natural Science Foundation of China(82273856,22077143,21977127,22377023);the Research Project(31511010402,China);Fundamental Research Funds for Hainan University(KYQD(ZR)-21031,KYQD(ZR)-21108 and XTCX2022JKA01,China);Science Foundation of Hainan Province(KJRC2023B10,China).

摘　　要：Accurate receptor/ligand binding free energy calculations can greatly accelerate drug discov-ery by identifying highly potent ligands.By simulating the change from one compound structure to another,the relative binding free energy(RBFE)change can be calculated based on the theoretically rigorous free energy perturbation(FEP)method.However,existing FEP-RBFE approaches may face convergence challenges due to difficulties in simulating non-physical intermediate states,which can lead to increased computational costs to obtain the converged results.To fundamentally overcome these issues and accelerate drug discovery,a new combined-structure RBFE(CS-FEP)calculation strategy was proposed,which solved the existing issues by constructing a new alchemical pathway,smoothed the alchemical transformation,increased the phase-space overlap between adjacent states,and thus signif-icantly increased the convergence and accelerated the relative binding free energy calculations.This method was extensively tested in a practical drug discovery effort by targeting phosphodiesterase-1(PDE1).Starting from a PDE1 inhibitor(compound 9,IC_(50)=16.8 mmol/L),the CS-FEP guided hit-to-lead optimizations resulted in a promising lead(11b and its mesylate salt formulation 11b-Mesylate,IC_(50)=7.0 nmol/L),with w2400-fold improved inhibitory activity.Further experimental studies re-vealed that the lead showed reasonable metabolic stability and significant anti-fibrotic effects in vivo.

关 键 词：Free energy perturbation Drug design Phosphodiesterase 1 Relative binding free energy Molecular simulation 

分 类 号：R943[医药卫生—药剂学]