Free Energy Perturbation (FEP)-guided Scaffold Hopping

Overview

Journal Acta Pharm Sin B

Publisher Elsevier

Specialty Pharmacology

Date 2022 May 9

PMID 35530128

Authors

Deyan Wu

Xuehua Zheng

Runduo Liu

Zhe Li

Zan Jiang

Qian Zhou

Yue Huang

Xu-Nian Wu

Chen Zhang

Yi-You Huang

Hai-Bin Luo

Affiliations

Soon will be listed here.

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.

Citing Articles

Robust protein-ligand interaction modeling through integrating physical laws and geometric knowledge for absolute binding free energy calculation.

Su Q, Wang J, Gou Q, Hu R, Jiang L, Zhang H Chem Sci. 2025; .

PMID: 40007661 PMC: 11848741. DOI: 10.1039/d4sc07405j.

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

Li Z, Jiang M, Liu R, Wang Q, Zhou Q, Huang Y Acta Pharm Sin B. 2025; 14(12):5357-5369.

PMID: 39807312 PMC: 11725145. DOI: 10.1016/j.apsb.2024.06.021.

PairMap: An Intermediate Insertion Approach for Improving the Accuracy of Relative Free Energy Perturbation Calculations for Distant Compound Transformations.

Furui K, Shimizu T, Akiyama Y, Kimura S, Terada Y, Ohue M J Chem Inf Model. 2025; 65(2):705-721.

PMID: 39800967 PMC: 11776053. DOI: 10.1021/acs.jcim.4c01634.

MoDAFold: a strategy for predicting the structure of missense mutant protein based on AlphaFold2 and molecular dynamics.

Zheng L, Shi S, Sun X, Lu M, Liao Y, Zhu S Brief Bioinform. 2024; 25(2).

PMID: 38305456 PMC: 10835750. DOI: 10.1093/bib/bbae006.

The maximal and current accuracy of rigorous protein-ligand binding free energy calculations.

Ross G, Lu C, Scarabelli G, Albanese S, Houang E, Abel R Commun Chem. 2023; 6(1):222.

PMID: 37838760 PMC: 10576784. DOI: 10.1038/s42004-023-01019-9.

References

Onufriev A, Bashford D, Case D . Exploring protein native states and large-scale conformational changes with a modified generalized born model. Proteins. 2004; 55(2):383-94. DOI: 10.1002/prot.20033. View

Liu M, Yuan M, Luo M, Bu X, Luo H, Hu X . Binding of curcumin with glyoxalase I: Molecular docking, molecular dynamics simulations, and kinetics analysis. Biophys Chem. 2010; 147(1-2):28-34. DOI: 10.1016/j.bpc.2009.12.007. View

Wu Y, Wang Q, Jiang M, Huang Y, Zhu Z, Han C . Discovery of Potent Phosphodiesterase-9 Inhibitors for the Treatment of Hepatic Fibrosis. J Med Chem. 2021; 64(13):9537-9549. DOI: 10.1021/acs.jmedchem.1c00862. View

Langdon S, Ertl P, Brown N . Bioisosteric Replacement and Scaffold Hopping in Lead Generation and Optimization. Mol Inform. 2016; 29(5):366-85. DOI: 10.1002/minf.201000019. View

Miller 3rd B, McGee Jr T, Swails J, Homeyer N, Gohlke H, Roitberg A . MMPBSA.py: An Efficient Program for End-State Free Energy Calculations. J Chem Theory Comput. 2015; 8(9):3314-21. DOI: 10.1021/ct300418h. View

Schneider , Neidhart , Giller , SCHMID . "Scaffold-Hopping" by Topological Pharmacophore Search: A Contribution to Virtual Screening. Angew Chem Int Ed Engl. 1999; 38(19):2894-2896. View

Azzouni F, Abu Samra K . Are phosphodiesterase type 5 inhibitors associated with vision-threatening adverse events? A critical analysis and review of the literature. J Sex Med. 2011; 8(10):2894-903. DOI: 10.1111/j.1743-6109.2011.02382.x. View

Abascal J, Vega C . A general purpose model for the condensed phases of water: TIP4P/2005. J Chem Phys. 2006; 123(23):234505. DOI: 10.1063/1.2121687. View

Udeoji D, Schwarz E . Tadalafil as monotherapy and in combination regimens for the treatment of pulmonary arterial hypertension. Ther Adv Respir Dis. 2012; 7(1):39-49. DOI: 10.1177/1753465812463627. View

10.

Dong X, Zhan W, Zhao M, Che J, Dai X, Wu Y . Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design. J Med Chem. 2019; 62(15):7264-7288. DOI: 10.1021/acs.jmedchem.9b00891. View

11.

Case D, Cheatham 3rd T, Darden T, Gohlke H, Luo R, Merz Jr K . The Amber biomolecular simulation programs. J Comput Chem. 2005; 26(16):1668-88. PMC: 1989667. DOI: 10.1002/jcc.20290. View

12.

Wang J, Wolf R, Caldwell J, Kollman P, Case D . Development and testing of a general amber force field. J Comput Chem. 2004; 25(9):1157-74. DOI: 10.1002/jcc.20035. View

13.

Hu Y, Stumpfe D, Bajorath J . Recent Advances in Scaffold Hopping. J Med Chem. 2016; 60(4):1238-1246. DOI: 10.1021/acs.jmedchem.6b01437. View

14.

Goga N, Rzepiela A, de Vries A, Marrink S, Berendsen H . Efficient Algorithms for Langevin and DPD Dynamics. J Chem Theory Comput. 2015; 8(10):3637-49. DOI: 10.1021/ct3000876. View

15.

Shang N, Shao Y, Cai Y, Guan M, Huang M, Cui W . Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure. Biochem Pharmacol. 2014; 89(1):86-98. DOI: 10.1016/j.bcp.2014.02.013. View

16.

Friesner R, Banks J, Murphy R, Halgren T, Klicic J, Mainz D . Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004; 47(7):1739-49. DOI: 10.1021/jm0306430. View

17.

Berthet M, Cheviet T, Dujardin G, Parrot I, Martinez J . Isoxazolidine: A Privileged Scaffold for Organic and Medicinal Chemistry. Chem Rev. 2016; 116(24):15235-15283. DOI: 10.1021/acs.chemrev.6b00543. View

18.

Zafrani Y, Yeffet D, Sod-Moriah G, Berliner A, Amir D, Marciano D . Difluoromethyl Bioisostere: Examining the "Lipophilic Hydrogen Bond Donor" Concept. J Med Chem. 2017; 60(2):797-804. DOI: 10.1021/acs.jmedchem.6b01691. View

19.

Geppert H, Vogt M, Bajorath J . Current trends in ligand-based virtual screening: molecular representations, data mining methods, new application areas, and performance evaluation. J Chem Inf Model. 2010; 50(2):205-16. DOI: 10.1021/ci900419k. View

20.

Tan C, Yang L, Luo R . How well does Poisson-Boltzmann implicit solvent agree with explicit solvent? A quantitative analysis. J Phys Chem B. 2006; 110(37):18680-7. DOI: 10.1021/jp063479b. View