Dataset Information

Continuous Evaluation of Ligand Protein Predictions: A Weekly Community Challenge for Drug Docking.

ABSTRACT: Docking calculations can accelerate drug discovery by predicting the bound poses of ligands for a targeted protein. However, it is not clear which docking methods work best. Furthermore, predicting poses requires steps outside the docking algorithm itself, such as preparation of the protein and ligand, and it is not known which components are most in need of improvement. The Continuous Evaluation of Ligand Protein Predictions (CELPP) is a blinded prediction challenge designed to address these issues. Participants create a workflow to predict protein-ligand binding poses, which is then tasked with predicting 10-100 new protein-ligand crystal structures each week. CELPP evaluates the accuracy of each workflow's predictions and posts the scores online. The results can be used to identify the strengths and weaknesses of current approaches, help map docking problems to the algorithms most likely to overcome them, and illuminate areas of unmet need in structure-guided drug design.

SUBMITTER: Wagner JR

PROVIDER: S-EPMC6685748 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Continuous Evaluation of Ligand Protein Predictions: A Weekly Community Challenge for Drug Docking.

Wagner Jeffrey R JR Churas Christopher P CP Liu Shuai S Swift Robert V RV Chiu Michael M Shao Chenghua C Feher Victoria A VA Burley Stephen K SK Gilson Michael K MK Amaro Rommie E RE

Structure (London, England : 1993) 20190627 8

Docking calculations can accelerate drug discovery by predicting the bound poses of ligands for a targeted protein. However, it is not clear which docking methods work best. Furthermore, predicting poses requires steps outside the docking algorithm itself, such as preparation of the protein and ligand, and it is not known which components are most in need of improvement. The Continuous Evaluation of Ligand Protein Predictions (CELPP) is a blinded prediction challenge designed to address these is ...[more]

PMID: 31257108

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Project description:We describe binding free energy calculations in the D3R Grand Challenge 2015 for blind prediction of the binding affinities of 180 ligands to Hsp90. The present D3R challenge was built around experimental datasets involving Heat shock protein (Hsp) 90, an ATP-dependent molecular chaperone which is an important anticancer drug target. The Hsp90 ATP binding site is known to be a challenging target for accurate calculations of ligand binding affinities because of the ligand-dependent conformational changes in the binding site, the presence of ordered waters and the broad chemical diversity of ligands that can bind at this site. Our primary focus here is to distinguish binders from nonbinders. Large scale absolute binding free energy calculations that cover over 3000 protein-ligand complexes were performed using the BEDAM method starting from docked structures generated by Glide docking. Although the ligand dataset in this study resembles an intermediate to late stage lead optimization project while the BEDAM method is mainly developed for early stage virtual screening of hit molecules, the BEDAM binding free energy scoring has resulted in a moderate enrichment of ligand screening against this challenging drug target. Results show that, using a statistical mechanics based free energy method like BEDAM starting from docked poses offers better enrichment than classical docking scoring functions and rescoring methods like Prime MM-GBSA for the Hsp90 data set in this blind challenge. Importantly, among the three methods tested here, only the mean value of the BEDAM binding free energy scores is able to separate the large group of binders from the small group of nonbinders with a gap of 2.4 kcal/mol. None of the three methods that we have tested provided accurate ranking of the affinities of the 147 active compounds. We discuss the possible sources of errors in the binding free energy calculations. The study suggests that BEDAM can be used strategically to discriminate binders from nonbinders in virtual screening and to more accurately predict the ligand binding modes prior to the more computationally expensive FEP calculations of binding affinity.

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Dataset Information

Continuous Evaluation of Ligand Protein Predictions: A Weekly Community Challenge for Drug Docking.

Publications

Continuous Evaluation of Ligand Protein Predictions: A Weekly Community Challenge for Drug Docking.

Similar Datasets

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