Dataset Information

EDock-ML: A web server for using ensemble docking with machine learning to aid drug discovery.

ABSTRACT: EDock-ML is a web server that facilitates the use of ensemble docking with machine learning to help decide whether a compound is worthwhile to be considered further in a drug discovery process. Ensemble docking provides an economical way to account for receptor flexibility in molecular docking. Machine learning improves the use of the resulting docking scores to evaluate whether a compound is likely to be useful. EDock-ML takes a bottom-up approach in which machine-learning models are developed one protein at a time to improve predictions for the proteins included in its database. Because the machine-learning models are intended to be used without changing the docking and model parameters with which the models were trained, novice users can use it directly without worrying about what parameters to choose. A user simply submits a compound specified by an ID from the ZINC database (Sterling, T.; Irwin, J. J., J Chem Inf Model 2015, 55[11], 2,324-2,337.) or upload a file prepared by a chemical drawing program and receives an output helping the user decide the likelihood of the compound to be active or inactive for a drug target. EDock-ML can be accessed freely at edock-ml.umsl.edu.

SUBMITTER: Chandak T

PROVIDER: S-EPMC8040857 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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EDock-ML: A web server for using ensemble docking with machine learning to aid drug discovery.

Chandak Tanay T Wong Chung F CF

Protein science : a publication of the Protein Society 20210325 5

EDock-ML is a web server that facilitates the use of ensemble docking with machine learning to help decide whether a compound is worthwhile to be considered further in a drug discovery process. Ensemble docking provides an economical way to account for receptor flexibility in molecular docking. Machine learning improves the use of the resulting docking scores to evaluate whether a compound is likely to be useful. EDock-ML takes a bottom-up approach in which machine-learning models are developed ...[more]

PMID: 33733530

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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

EDock-ML: A web server for using ensemble docking with machine learning to aid drug discovery.

Publications

EDock-ML: A web server for using ensemble docking with machine learning to aid drug discovery.

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