Free energy perturbation (FEP)-guided scaffold hopping.
10.1016/j.apsb.2021.09.027
- Author:
Deyan WU
1
;
Xuehua ZHENG
2
;
Runduo LIU
3
;
Zhe LI
3
;
Zan JIANG
2
;
Qian ZHOU
3
;
Yue HUANG
3
;
Xu-Nian WU
3
;
Chen ZHANG
3
;
Yi-You HUANG
1
;
Hai-Bin LUO
1
Author Information
1. School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
2. School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
3. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
- Publication Type:Journal Article
- Keywords:
ABFE, absolute binding free energy;
BAR, Bennet acceptance ratio;
Binding potencies;
DCM, dichloromethane;
DMF, N,N-dimethylformamide;
DMSO, dimethyl sulfoxide;
Drug discovery;
FEP, free energy perturbation;
Free energy perturbation;
GAFF, general AMBER force field;
HPLC, high performance liquid chromatography;
HRMS, High resolution mass spectra;
IC50, half-inhibitory concentration;
IPTG, isopropyl b-d-thiogalactopyranoside;
LV, left ventricle;
MAD, mean absolute deviations;
MD, molecular dynamics;
MM-GBSA, molecular mechanics/generalized born surface area;
Molecular design;
PAH, pulmonary arterial hypertension;
PDB, protein data bank;
PDE, phosphodiesterase;
PDE5 inhibitors;
PDE5, phosphodiesterase-5;
PME, particle mesh Ewald;
Privileged scaffolds;
Pulmonary arterial hypertension;
RBFE, relative binding free energy;
RED, restraint energy distribution;
RESP, restrained electrostatic potential;
RV, right ventricle;
RVHI, right ventricle hypertrophy index;
SARs, structure–activity relationships;
Scaffold hopping;
THF, tetrahydrofuran;
TLC, thin-layer chromatography;
WT, wall thickness;
ip, intraperitoneal injection;
iv, intravenous administration;
mPAP, pulmonary artery pressure;
po, oral administration (per os)
- From:
Acta Pharmaceutica Sinica B
2022;12(3):1351-1362
- CountryChina
- Language:English
-
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 great advantages to precisely predict the theoretical binding potencies ΔG FEP between ligands and their target, which were more consistent with the experimental binding potencies ΔG EXP (the mean absolute deviations | Δ G FEP - Δ G EXP | < 2 kcal/mol) than those ΔG MM-PBSA or ΔG MM-GBSA predicted by the MM-PBSA 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.
