Accurate Calculation of the Absolute Free Energy of Binding for Drug Molecules

Overview

Journal Chem Sci

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2016 Jan 23

PMID 26798447

Citations 118

Authors

Matteo Aldeghi

Alexander Heifetz

Michael J Bodkin

Stefan Knapp

Philip C Biggin

Affiliations

Soon will be listed here.

Abstract

Accurate prediction of binding affinities has been a central goal of computational chemistry for decades, yet remains elusive. Despite good progress, the required accuracy for use in a drug-discovery context has not been consistently achieved for drug-like molecules. Here, we perform absolute free energy calculations based on a thermodynamic cycle for a set of diverse inhibitors binding to bromodomain-containing protein 4 (BRD4) and demonstrate that a mean absolute error of 0.6 kcal mol can be achieved. We also show a similar level of accuracy (1.0 kcal mol) can be achieved in pseudo prospective approach. Bromodomains are epigenetic mark readers that recognize acetylation motifs and regulate gene transcription, and are currently being investigated as therapeutic targets for cancer and inflammation. The unprecedented accuracy offers the exciting prospect that the binding free energy of drug-like compounds can be predicted for pharmacologically relevant targets.

Citing Articles

Molecular Glue-Design-Evaluator (MOLDE): An Advanced Method for In-Silico Molecular Glue Design.

Ben Geoffrey A, Agrawal D, Kulkarni N, Gunasekaran M ACS Omega. 2025; 10(7):6650-6662.

PMID: 40028145 PMC: 11865985. DOI: 10.1021/acsomega.4c08049.

Narrowing the gap between machine learning scoring functions and free energy perturbation using augmented data.

Valsson I, Warren M, Deane C, Magarkar A, Morris G, Biggin P Commun Chem. 2025; 8(1):41.

PMID: 39922899 PMC: 11807228. DOI: 10.1038/s42004-025-01428-y.

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.

Fragmenstein: predicting protein-ligand structures of compounds derived from known crystallographic fragment hits using a strict conserved-binding-based methodology.

Ferla M, Sanchez-Garcia R, Skyner R, Gahbauer S, Taylor J, von Delft F J Cheminform. 2025; 17(1):4.

PMID: 39806443 PMC: 11731148. DOI: 10.1186/s13321-025-00946-0.

Adaptive Lambda Scheduling: A Method for Computational Efficiency in Free Energy Perturbation Simulations.

Midgley S, Bariami S, Habgood M, Mackey M J Chem Inf Model. 2025; 65(2):512-516.

PMID: 39786727 PMC: 11776047. DOI: 10.1021/acs.jcim.4c01668.

References

Wang K, Chodera J, Yang Y, Shirts M . Identifying ligand binding sites and poses using GPU-accelerated Hamiltonian replica exchange molecular dynamics. J Comput Aided Mol Des. 2013; 27(12):989-1007. PMC: 4154199. DOI: 10.1007/s10822-013-9689-8. View

Fox S, Pittock C, Tautermann C, Fox T, Christ C, Malcolm N . Free energies of binding from large-scale first-principles quantum mechanical calculations: application to ligand hydration energies. J Phys Chem B. 2013; 117(32):9478-85. DOI: 10.1021/jp404518r. View

Vriend G . WHAT IF: a molecular modeling and drug design program. J Mol Graph. 1990; 8(1):52-6, 29. DOI: 10.1016/0263-7855(90)80070-v. View

Ross G, Morris G, Biggin P . One Size Does Not Fit All: The Limits of Structure-Based Models in Drug Discovery. J Chem Theory Comput. 2013; 9(9):4266-4274. PMC: 3793897. DOI: 10.1021/ct4004228. View

Wereszczynski J, McCammon J . Statistical mechanics and molecular dynamics in evaluating thermodynamic properties of biomolecular recognition. Q Rev Biophys. 2011; 45(1):1-25. PMC: 3291752. DOI: 10.1017/S0033583511000096. View

Hess B . P-LINCS: A Parallel Linear Constraint Solver for Molecular Simulation. J Chem Theory Comput. 2015; 4(1):116-22. DOI: 10.1021/ct700200b. View

Filippakopoulos P, Knapp S . The bromodomain interaction module. FEBS Lett. 2012; 586(17):2692-704. DOI: 10.1016/j.febslet.2012.04.045. View

Myszka D, Abdiche Y, Arisaka F, Byron O, Eisenstein E, HENSLEY P . The ABRF-MIRG'02 study: assembly state, thermodynamic, and kinetic analysis of an enzyme/inhibitor interaction. J Biomol Tech. 2004; 14(4):247-69. PMC: 2279960. View

Woo H, Roux B . Calculation of absolute protein-ligand binding free energy from computer simulations. Proc Natl Acad Sci U S A. 2005; 102(19):6825-30. PMC: 1100764. DOI: 10.1073/pnas.0409005102. View

10.

Hess B, Kutzner C, van der Spoel D, Lindahl E . GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. J Chem Theory Comput. 2015; 4(3):435-47. DOI: 10.1021/ct700301q. View

11.

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

12.

Jorgensen W . Efficient drug lead discovery and optimization. Acc Chem Res. 2009; 42(6):724-33. PMC: 2727934. DOI: 10.1021/ar800236t. View

13.

Huang L, Roux B . AUTOMATED FORCE FIELD PARAMETERIZATION FOR NON-POLARIZABLE AND POLARIZABLE ATOMIC MODELS BASED ON TARGET DATA. J Chem Theory Comput. 2013; 9(8). PMC: 3819940. DOI: 10.1021/ct4003477. View

14.

Vidler L, Filippakopoulos P, Fedorov O, Picaud S, Martin S, Tomsett M . Discovery of novel small-molecule inhibitors of BRD4 using structure-based virtual screening. J Med Chem. 2013; 56(20):8073-88. PMC: 3807807. DOI: 10.1021/jm4011302. View

15.

Bissantz C, Kuhn B, Stahl M . A medicinal chemist's guide to molecular interactions. J Med Chem. 2010; 53(14):5061-84. PMC: 2905122. DOI: 10.1021/jm100112j. View

16.

Zhao C, Caplan D, Noskov S . Evaluations of the Absolute and Relative Free Energies for Antidepressant Binding to the Amino Acid Membrane Transporter LeuT with Free Energy Simulations. J Chem Theory Comput. 2015; 6(6):1900-14. DOI: 10.1021/ct9006597. View

17.

Lee M, Olson M . Calculation of absolute protein-ligand binding affinity using path and endpoint approaches. Biophys J. 2005; 90(3):864-77. PMC: 1367111. DOI: 10.1529/biophysj.105.071589. View

18.

Mobley D, Graves A, Chodera J, McReynolds A, Shoichet B, Dill K . Predicting absolute ligand binding free energies to a simple model site. J Mol Biol. 2007; 371(4):1118-34. PMC: 2104542. DOI: 10.1016/j.jmb.2007.06.002. View

19.

Gerber P, Muller K . MAB, a generally applicable molecular force field for structure modelling in medicinal chemistry. J Comput Aided Mol Des. 1995; 9(3):251-68. DOI: 10.1007/BF00124456. View

20.

Ciceri P, Muller S, OMahony A, Fedorov O, Filippakopoulos P, Hunt J . Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. Nat Chem Biol. 2014; 10(4):305-12. PMC: 3998711. DOI: 10.1038/nchembio.1471. View