Dataset Information

Prediction of Protein-compound Binding Energies from Known Activity Data: Docking-score-based Method and its Applications.

ABSTRACT: We used protein-compound docking simulations to develop a structure-based quantitative structure-activity relationship (QSAR) model. The prediction model used docking scores as descriptors. The binding free energy was approximated by a weighted average of docking scores for multiple proteins. This approximation was based on a pharmacophore model of receptor pockets and compounds. The weights of the docking scores were restricted to small values to avoid unrealistic weights by a regularization term. Additional outlier elimination improved the results. We applied this method to two groups of targets. The first target was the kinase family. The cross-validation results of 107 kinase proteins showed that the RMSE of predicted binding free energies was 1.1?kcal/mol. The second target was the matrix metalloproteinase (MMP) family, which has been difficult for docking programs. MMPs require metal-binding groups in their inhibitor structures in many cases. A quantum effect contributes to the metal-ligand interaction. Despite this difficulty, the present method worked well for the MMPs. This method showed that the RMSE of predicted binding free energies was 1.1?kcal/mol. In comparison, with the original docking method the RMSE was 1.7?kcal/mol. The results suggest that the present QSAR model should be applied to general target proteins.

SUBMITTER: Fukunishi Y

PROVIDER: S-EPMC6055825 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Prediction of Protein-compound Binding Energies from Known Activity Data: Docking-score-based Method and its Applications.

Fukunishi Yoshifumi Y Yamashita Yasunobu Y Mashimo Tadaaki T Nakamura Haruki H

Molecular informatics 20180214 6-7

We used protein-compound docking simulations to develop a structure-based quantitative structure-activity relationship (QSAR) model. The prediction model used docking scores as descriptors. The binding free energy was approximated by a weighted average of docking scores for multiple proteins. This approximation was based on a pharmacophore model of receptor pockets and compounds. The weights of the docking scores were restricted to small values to avoid unrealistic weights by a regularization te ...[more]

PMID: 29442436

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Project description:To accelerate conformation sampling of slow dynamics from receptor or ligand, we introduced flattening potentials on selected bonded and nonbonded intramolecular interactions to the binding energy distribution analysis method (BEDAM) for calculating absolute binding free energies of protein-ligand complexes using an implicit solvent model and implemented flattening BEDAM using the asynchronous replica exchange (AsyncRE) framework for performing large scale replica exchange molecular dynamics (REMD) simulations. The advantage of using the flattening feature to reduce high energy barriers was exhibited first by the p-xylene-T4 lysozyme complex, where the intramolecular interactions of a protein side chain on the binding site were flattened to accelerate the conformational transition of the side chain from the trans to the gauche state when the p-xylene ligand is present in the binding site. Much more extensive flattening BEDAM simulations were performed for 53 experimental binders and 248 nonbinders of HIV-1 integrase which formed the SAMPL4 challenge, with the total simulation time of 24.3 ?s. We demonstrated that the flattening BEDAM simulations not only substantially increase the number of true positives (and reduce false negatives) but also improve the prediction accuracy of binding poses of experimental binders. Furthermore, the values of area under the curve (AUC) of receiver operating characteristic (ROC) and the enrichment factors at 20% cutoff calculated from the flattening BEDAM simulations were improved significantly in comparison with that of simulations without flattening as we previously reported for the whole SAMPL4 database. Detailed analysis found that the improved ability to discriminate the binding free energies between the binders and nonbinders is due to the fact that the flattening simulations reduce the reorganization free energy penalties of binders and decrease the overlap of binding free energy distributions of binders relative to that of nonbinders. This happens because the conformational ensemble distributions for both the ligand and protein in solution match those at the fully coupled (complex) state more closely when the systems are more fully sampled after the flattening potentials are applied to the intermediate states.

Dataset Information

Prediction of Protein-compound Binding Energies from Known Activity Data: Docking-score-based Method and its Applications.

Publications

Prediction of Protein-compound Binding Energies from Known Activity Data: Docking-score-based Method and its Applications.

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