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Accurate calculation of the absolute free energy of binding for drug molecules.

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^-1 can be achieved. We also show a similar level of accuracy (1.0 kcal mol^-1) 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.

SUBMITTER: Aldeghi M

PROVIDER: S-EPMC4700411 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Accurate calculation of the absolute free energy of binding for drug molecules.

Aldeghi Matteo M Heifetz Alexander A Bodkin Michael J MJ Knapp Stefan S Biggin Philip C PC

Chemical science 20151007 1

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<sup>-1</ ...[more]

PMID: 26798447

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Project description:Understanding the physical forces underlying receptor-ligand binding requires robust methods for analyzing the binding thermodynamics. In end-point binding free energy methods the binding free energy is naturally decomposable into physically intuitive contributions such as the solvation free energy and configurational entropy that can provide insights. Here we present a new end-point method called EE-BQH (Effective Energy-Boltzmann-Quasiharmonic) which combines the Boltzmann-Quasiharmonic model for configurational entropy with different solvation free energy methods, such as the continuum solvent PBSA model and the integral equation-based 3D-RISM, to estimate the absolute binding free energy. We compare EE-BQH with other treatments of configurational entropy such as Quasiharmonic models in internal coordinates (QHIC) and in Cartesian coordinates (QHCC), and Normal Mode analysis (NMA), by testing them on the octa acids host-guest complexes from the SAMPL8 blind challenge. The accuracies in the calculated absolute binding free energies strongly depend on the configurational entropy and solvation free energy methods used. QHIC and BQH yield the best agreements with the established potential of mean force (PMF) estimates, with R2 of ∼0.7 and mean unsigned error of ∼1.7 kcal mol-1. These results from the end-point calculations are also in similar agreement with experiments. While 3D-RISM in combination with QHIC or BQH lead to reasonable correlations with the PMF results and experiments, the calculated absolute binding free energies are underestimated by ∼5 kcal mol-1. While the binding is accompanied by a significant reduction in the ligand translational/rotational entropy, the change in the torsional entropy in these host-guest systems is slightly positive. Compared with BQH, QHIC underestimates the reduction of configurational entropy because of the non-Gaussian probability distributions in the ligand rotation and a small number of torsions. The study highlights the crucial role of configurational entropy in determining binding and demonstrates the potential of using the new end-point method to provide insights in more complex protein-ligand systems.

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Accurate calculation of the absolute free energy of binding for drug molecules.

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Accurate calculation of the absolute free energy of binding for drug molecules.

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