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A practical guide to large-scale docking

A Publisher Correction to this article was published on 09 December 2021

This article has been updated

Abstract

Structure-based docking screens of large compound libraries have become common in early drug and probe discovery. As computer efficiency has improved and compound libraries have grown, the ability to screen hundreds of millions, and even billions, of compounds has become feasible for modest-sized computer clusters. This allows the rapid and cost-effective exploration and categorization of vast chemical space into a subset enriched with potential hits for a given target. To accomplish this goal at speed, approximations are used that result in undersampling of possible configurations and inaccurate predictions of absolute binding energies. Accordingly, it is important to establish controls, as are common in other fields, to enhance the likelihood of success in spite of these challenges. Here we outline best practices and control docking calculations that help evaluate docking parameters for a given target prior to undertaking a large-scale prospective screen, with exemplification in one particular target, the melatonin receptor, where following this procedure led to direct docking hits with activities in the subnanomolar range. Additional controls are suggested to ensure specific activity for experimentally validated hit compounds. These guidelines should be useful regardless of the docking software used. Docking software described in the outlined protocol (DOCK3.7) is made freely available for academic research to explore new hits for a range of targets.

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Fig. 1: Large library docking workflow.
Fig. 2: Enrichment of actives against decoys.
Fig. 3: Control sets for retrospective docking calculations.
Fig. 4: Suggested experimental validation of docking hits.
Fig. 5: Outline of the procedure for DOCK3.7 virtual ligand discovery campaigns.
Fig. 6: Controls for docking optimization.
Fig. 7: Matching and dielectric boundary spheres drive changes to sampling and scoring in DOCK3.7.
Fig. 8: Polarizing effects specific atoms’ electrostatic potential.
Fig. 9: Navigating the ZINC20 Tranche Viewer.

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Data availability

An example set of files used in this protocol, including ligand and decoy sets, default docking grids and optimized docking grids, can be downloaded from http://files.docking.org/dock/mt1_protocol.tar.gz. The example dataset uses the MT1 structure (PDB: 6ME3) co-crystallized with 2-phenylmelatonin.

Software availability

DOCK3.7 can be downloaded after applying for a license from http://dock.docking.org/Online_Licensing/index.htm. Licenses are free for nonprofit research.

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Acknowledgements

This work was supported by NIH grants R35GM122481 (to B.K.S.) and GM133836 (to J.J.I.). J.C. was supported by grants from the Swedish Research Council (2017-04676) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement: 715052). B.J.B. was partly supported by an NIH NRSA fellowship F32GM136062. C.M.W. was partly supported by the National Institutes of Health Training Grant T32 GM007175, NSF GRFP and UCSF Discovery Fellowship. We thank members of the Shoichet lab for feedback on the procedures described.

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B.J.B. and S.G. wrote the manuscript with additional input from all authors. B.J.B., S.G., A.L., J.L., C.W., R.M.S., E.F., T.E.B., J.C., J.J.I. and B.K.S. developed the protocol. B.J.B., S.G., A.L., J.L., C.W., R.M.S. and T.E.B. contributed scripts. E.F. tested the protocol. Research was supervised by J.C., J.J.I. and B.K.S.

Corresponding author

Correspondence to Brian K. Shoichet.

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B.K.S. and J.J.I. are founders of Blue Dolphin Lead Discovery LLC, which undertakes fee-for-service ligand discovery.

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Peer review information Nature Protocols thanks Claudio Cavasotto, Vincent Zoete and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Key references using this protocol

Stein, R. M. et al. Nature 579, 609–614 (2020): https://doi.org/10.1038/s41586-020-2027-0

Lyu, J. et al. Nature 566, 224–229 (2019): https://www.nature.com/articles/s41586-019-0917-9

Schuller, M. et al. Sci. Adv. 7, eabf8711 (2021): https://advances.sciencemag.org/content/7/16/eabf8711

Key data used in this protocol

Stein, R. M. et al. Nature 579, 609–614 (2020): https://doi.org/10.1038/s41586-020-2027-0

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Supplementary Information

INDOCK Guide and Blastermaster Guide.

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Bender, B.J., Gahbauer, S., Luttens, A. et al. A practical guide to large-scale docking. Nat Protoc 16, 4799–4832 (2021). https://doi.org/10.1038/s41596-021-00597-z

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