Interactive Molecular Dynamics in Virtual Reality Is an Effective Tool for Flexible Substrate and Inhibitor Docking to the SARS-CoV-2 Main Protease.

Journal of Chemical Information and Modeling
Helen DeeksAdrian Mulholland

Abstract

The main protease (Mpro) of the SARS-CoV-2 virus is one focus of drug development efforts for COVID-19. Here, we show that interactive molecular dynamics in virtual reality (iMD-VR) is a useful and effective tool for creating Mpro complexes. We make these tools and models freely available. iMD-VR provides an immersive environment in which users can interact with MD simulations and so build protein complexes in a physically rigorous and flexible way. Recently, we have demonstrated that iMD-VR is an effective method for interactive, flexible docking of small molecule drugs into their protein targets (Deeks et al. PLoS One 2020, 15, e0228461). Here, we apply this approach to both an Mpro inhibitor and an oligopeptide substrate, using experimentally determined crystal structures. For the oligopeptide, we test against a crystallographic structure of the original SARS Mpro. Docking with iMD-VR gives models in agreement with experimentally observed (crystal) structures. The docked structures are also tested in MD simulations and found to be stable. Different protocols for iMD-VR docking are explored, e.g., with and without restraints on protein backbone, and we provide recommendations for its use. We find that it is important for the ...Continue Reading

References

Feb 14, 2002·The Journal of General Virology·Annette Hegyi, John Ziebuhr
May 6, 2003·Science·Marco A MarraRachel L Roper
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Apr 14, 2006·Current Topics in Medicinal Chemistry·Po-Huang Liang
Jul 14, 2006·Antiviral Research·Bart L Haagmans, Albert D M E Osterhaus
Dec 6, 2006·Biochemistry·Vito GrazianoWalter F Mangel
Mar 1, 2007·Emerging Infectious Diseases·Lin-Fa WangBryan T Eaton
Oct 16, 2010·PloS One·Chi-Pang ChuckKam-Bo Wong
Jul 19, 2011·Future Virology·Dale L Barnard, Yohichi Kumaki
Feb 11, 2012·Methods in Molecular Biology·Irina Kufareva, Ruben Abagyan
Feb 28, 2015·Methods in Molecular Biology·Anthony R Fehr, Stanley Perlman
Nov 18, 2015·Journal of Chemical Theory and Computation·James A MaierCarlos Simmerling
Oct 7, 2016·Nature Communications·Kathryn M HartGregory R Bowman
May 17, 2017·Biophysics Reviews·Nataraj S PagadalaJack Tuszynski
Apr 3, 2018·Biophysical Journal·Rommie E AmaroJeremy C Smith
May 8, 2018·Drug Discovery Today·Maciej CiemnySebastian Kmiecik
Jul 3, 2018·Science Advances·Michael O'ConnorDavid R Glowacki
Mar 17, 2019·Interdisciplinary Sciences, Computational Life Sciences·Jin LiLe Zhang
Mar 21, 2019·The Journal of Physical Chemistry. a·Silvia AmabilinoDavid R Glowacki
Mar 29, 2019·Journal of Molecular Graphics & Modelling·Laura J KingsleyGlen Spraggon
Jan 23, 2020·Journal of Medical Virology·Yu ChenDeyin Guo
Feb 6, 2020·Chembiochem : a European Journal of Chemical Biology·Jared S MorseWenshe Ray Liu
Feb 23, 2020·The Biochemical Journal·Boris KrichelCharlotte Uetrecht
Apr 2, 2020·PLoS Computational Biology·Kevin C CassidyJacob D Durrant
Apr 24, 2020·Journal of Chemical Theory and Computation·Gaoqi WengTingjun Hou
Jun 20, 2020·Nature Chemistry·John ChoderaFrank von Delft
Aug 1, 2020·International Journal of Molecular Sciences·Alessandro GrottesiCarmine Talarico
Sep 29, 2020·Computational and Structural Biotechnology Journal·Martín CalveloRebeca Garcia-Fandino

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Citations

Mar 31, 2021·Journal of Chemical Information and Modeling·Giorgio AmendolaSandro Cosconati
Jul 29, 2021·The Journal of Physical Chemistry. B·Aditya K PadhiTimir Tripathi
Jan 1, 2021·Journal of Chemical Information and Modeling·Adrian J Mulholland, Rommie E Amaro

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Software Mentioned

IMD
Nanome
VR
Narupa
Cognate
AMBER
GPL
NarupaXR
Mpro
OpenMM

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