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Using machine learning to improve ensemble docking for drug discovery.

ABSTRACT: Ensemble docking has provided an inexpensive method to account for receptor flexibility in molecular docking for virtual screening. Unfortunately, as there is no rigorous theory to connect the docking scores from multiple structures to measured activity, researchers have not yet come up with effective ways to use these scores to classify compounds into actives and inactives. This shortcoming has led to the decrease, rather than an increase in the performance of classifying compounds when more structures are added to the ensemble. Previously, we suggested machine learning, implemented in the form of a naïve Bayesian model could alleviate this problem. However, the naïve Bayesian model assumed that the probabilities of observing the docking scores to different structures to be independent. This approximation might prevent it from achieving even higher performance. In the work presented in this paper, we have relaxed this approximation when using several other machine learning methods-k nearest neighbor, logistic regression, support vector machine, and random forest-to improve ensemble docking. We found significant improvement.

SUBMITTER: Chandak T

PROVIDER: S-EPMC7815257 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Using machine learning to improve ensemble docking for drug discovery.

Chandak Tanay T Mayginnes John P JP Mayes Howard H Wong Chung F CF

Proteins 20200525 10

Ensemble docking has provided an inexpensive method to account for receptor flexibility in molecular docking for virtual screening. Unfortunately, as there is no rigorous theory to connect the docking scores from multiple structures to measured activity, researchers have not yet come up with effective ways to use these scores to classify compounds into actives and inactives. This shortcoming has led to the decrease, rather than an increase in the performance of classifying compounds when more st ...[more]

PMID: 32401384

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Project description:In recent years machine learning has transformed many aspects of the drug discovery process including small molecule design for which the prediction of the bioactivity is an integral part. Leveraging structural information about the interactions between a small molecule and its protein target has great potential for downstream machine learning scoring approaches, but is fundamentally limited by the accuracy with which protein:ligand complex structures can be predicted in a reliable and automated fashion. With the goal of finding practical approaches to generating useful kinase:inhibitor complex geometries for downstream machine learning scoring approaches, we present a kinase-centric docking benchmark assessing the performance of different classes of docking and pose selection strategies to assess how well experimentally observed binding modes are recapitulated in a realistic cross-docking scenario. The assembled benchmark data set focuses on the well-studied protein kinase family and comprises a subset of 589 protein structures co-crystallized with 423 ATP-competitive ligands. We find that the docking methods biased by the co-crystallized ligand-utilizing shape overlap with or without maximum common substructure matching-are more successful in recovering binding poses than standard physics-based docking alone. Also, docking into multiple structures significantly increases the chance to generate a low RMSD docking pose. Docking utilizing an approach that combines all three methods (Posit) into structures with the most similar co-crystallized ligands according to shape and electrostatics proofed to be the most efficient way to reproduce binding poses achieving a success rate of 66.9 % across all included systems. The studied docking and pose selection strategies-which utilize the OpenEye Toolkit-were implemented into pipelines of the KinoML framework allowing automated and reliable protein:ligand complex generation for future downstream machine learning tasks. Although focused on protein kinases, we believe the general findings can also be transferred to other protein families.

Dataset Information

Using machine learning to improve ensemble docking for drug discovery.

Publications

Using machine learning to improve ensemble docking for drug discovery.

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