Predictions of Ligand Selectivity from Absolute Binding Free Energy Calculations

Abstract

Binding selectivity is a requirement for the development of a safe drug, and it is a critical property for chemical probes used in preclinical target validation. Engineering selectivity adds considerable complexity to the rational design of new drugs, as it involves the optimization of multiple binding affinities. Computationally, the prediction of binding selectivity is a challenge, and generally applicable methodologies are still not available to the computational and medicinal chemistry communities. Absolute binding free energy calculations based on alchemical pathways provide a rigorous framework for affinity predictions and could thus offer a general approach to the problem. We evaluated the performance of free energy calculations based on molecular dynamics for the prediction of selectivity by estimating the affinity profile of three bromodomain inhibitors across multiple bromodomain families, and by comparing the results to isothermal titration calorimetry data. Two case studies were considered. In the first one, the affinities of two similar ligands for seven bromodomains were calculated and returned excellent agreement with experiment (mean unsigned error of 0.81 kcal/mol and Pearson correlation of 0.75). In this test case, we also show how the preferred binding orientation of a ligand for different proteins can be estimated via free energy calculations. In the second case, the affinities of a broad-spectrum inhibitor for 22 bromodomains were calculated and returned a more modest accuracy (mean unsigned error of 1.76 kcal/mol and Pearson correlation of 0.48); however, the reparametrization of a sulfonamide moiety improved the agreement with experiment.

Overview of the SAMPL6 host–guest binding affinity prediction challenge

“…The degree inaccuracy of these predictions largely determines how effective they can be in prioritizing synthesis of small molecule ligands [105]. Retrospective estimates have suggested that current methodologies are capable of achieving about 1–2 kcal/mol inaccuracy for well-behaved protein-ligand systems [6, 122], but more work remains to be done to extend the applicability domain of these technologies.…”

Resolving the Ligand-Binding Specificity in c-MYC G-Quadruplex DNA: Absolute Binding Free Energy Calculations and SPR Experiment

“…In recent years, statistical mechanics based absolute binding free energy methods such as DDM 42–44 have increasingly been applied to compute protein-small molecule binding free energy 45–50 , and we and others have shown that such methods can generate more accurate results compared with the more rapid docking and MM-PB(GB)/SA in estimating binding affinity for a number of protein-ligand systems 51–53 . However, the DDM method has not yet been applied to small molecule-DNA (or RNA) complexes.…”

Toward the Characterization of DAPT Interactions with γ‐Secretase

“…This result suggestst hat Asp257 is more likely to be found in its monoprotonated state at pH 7. [45,46] For this study,t he solvation free energy (DG solv )o fDAPT was calculated in water and in aP OPC lipid bilayer to corroborate the highera ffinity of the ligand for the membrane environment observed during our US simulations. [45,46] For this study,t he solvation free energy (DG solv )o fDAPT was calculated in water and in aP OPC lipid bilayer to corroborate the highera ffinity of the ligand for the membrane environment observed during our US simulations.…”