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Sampling and refinement protocols for template-based macrocycle docking: 2018 D3R Grand Challenge 4

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Abstract

We describe a new template-based method for docking flexible ligands such as macrocycles to proteins. It combines Monte-Carlo energy minimization on the manifold, a fast manifold search method, with BRIKARD for complex flexible ligand searching, and with the MELD accelerator of Replica-Exchange Molecular Dynamics simulations for atomistic degrees of freedom. Here we test the method in the Drug Design Data Resource blind Grand Challenge competition. This method was among the best performers in the competition, giving sub-angstrom prediction quality for the majority of the targets.

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Acknowledgements

This work was supported by National Institutes of Health grants R21 GM127952 and 1R01GM125813-01; National Science Foundation grants AF 1816314, AF 1645512, and DBI 1759277; and the National Science Foundation PRAC Award ACI-1713695. Part of this research has been enabled by the Blue Waters sustained-petascale computing project, which is supported by the National Science Foundation (Awards OCI-0725070 and ACI-1238993) and the state of Illinois. Blue Waters is a joint effort of the University of Illinois at Urbana–Champaign and its National Center for Supercomputing Applications. This work was funded by Division of Computing and Communication Foundations (Grant No. AF 1816314).

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Author notes

  1. Sergei Kotelnikov and Andrey Alekseenko have contributed equally to this work.

Authors and Affiliations

  1. Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, USA

    Sergei Kotelnikov, Andrey Alekseenko, Cong Liu, Mikhail Ignatov, Dzmitry Padhorny, Emiliano Brini, Evangelos Coutsias, Ken A. Dill & Dima Kozakov

  2. Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA

    Sergei Kotelnikov, Andrey Alekseenko, Mikhail Ignatov, Dzmitry Padhorny, Evangelos Coutsias & Dima Kozakov

  3. Innopolis University, Innopolis, Russia

    Sergei Kotelnikov

  4. Department of Chemistry, Stony Brook University, Stony Brook, NY, USA

    Cong Liu & Ken A. Dill

  5. Institute for Advanced Computational Sciences, Stony Brook University, Stony Brook, NY, USA

    Mikhail Ignatov & Dima Kozakov

  6. Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA

    Mark Lukin

  7. Department of Physics and Astronomy, Stony Brook University, Stony Brook, NY, USA

    Ken A. Dill

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  1. Sergei Kotelnikov
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Correspondence to Dima Kozakov.

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Kotelnikov, S., Alekseenko, A., Liu, C. et al. Sampling and refinement protocols for template-based macrocycle docking: 2018 D3R Grand Challenge 4. J Comput Aided Mol Des 34, 179–189 (2020). https://doi.org/10.1007/s10822-019-00257-1

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