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Discovery and validation of the binding poses of allosteric fragment hits to PTP1b: From molecular dynamics simulations to X-ray crystallography

Jack B. Greisman, Lindsay Willmore, Christine Y. Yeh, Fabrizio Giordanetto, Sahar Shahamadtar, Hunter Nisonoff, Paul Maragakis, View ORCID ProfileDavid E. Shaw
doi: https://doi.org/10.1101/2022.11.14.516467
Jack B. Greisman
1D. E. Shaw Research, New York, NY 10036, USA
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Lindsay Willmore
1D. E. Shaw Research, New York, NY 10036, USA
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Christine Y. Yeh
1D. E. Shaw Research, New York, NY 10036, USA
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Fabrizio Giordanetto
1D. E. Shaw Research, New York, NY 10036, USA
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Sahar Shahamadtar
1D. E. Shaw Research, New York, NY 10036, USA
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Hunter Nisonoff
1D. E. Shaw Research, New York, NY 10036, USA
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Paul Maragakis
1D. E. Shaw Research, New York, NY 10036, USA
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  • For correspondence: Paul.Maragakis@DEShawResearch.com David.Shaw@DEShawResearch.com
David E. Shaw
1D. E. Shaw Research, New York, NY 10036, USA
2Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA
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  • ORCID record for David E. Shaw
  • For correspondence: Paul.Maragakis@DEShawResearch.com David.Shaw@DEShawResearch.com
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Abstract

Fragment-based drug discovery has led to six approved drugs, but the small size of the chemical fragments used in such methods typically results in only weak interactions between the fragment and its target molecule, which makes it challenging to experimentally determine the three-dimensional poses fragments assume in the bound state. One computational approach that could help address this difficulty is long-timescale molecular dynamics (MD) simulation, which has been used in retrospective studies to recover experimentally known binding poses of fragments. Here, we present the results of long-timescale MD simulations that we used to prospectively discover binding poses for two series of fragments in allosteric pockets on a difficult and important pharmaceutical target, protein-tyrosine phosphatase 1b (PTP1b). Our simulations reversibly sampled the fragment association and dissociation process. One of the binding pockets found in the simulations has not to our knowledge been previously observed with a bound fragment, and the other pocket adopted a very rare conformation. We subsequently obtained high-resolution crystal structures of members of each fragment series bound to PTP1b, and the experimentally observed poses confirmed the simulation results. To the best of our knowledge, our findings provide the first demonstration that MD simulations can be used prospectively to determine fragment binding poses to previously unidentified pockets.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Fig. 2E, Fig. S3, and the referencing text were updated to include alternate conformations and all PTP1b structures deposited into the PDB through November 2022.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted February 22, 2023.
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Discovery and validation of the binding poses of allosteric fragment hits to PTP1b: From molecular dynamics simulations to X-ray crystallography
Jack B. Greisman, Lindsay Willmore, Christine Y. Yeh, Fabrizio Giordanetto, Sahar Shahamadtar, Hunter Nisonoff, Paul Maragakis, David E. Shaw
bioRxiv 2022.11.14.516467; doi: https://doi.org/10.1101/2022.11.14.516467
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Discovery and validation of the binding poses of allosteric fragment hits to PTP1b: From molecular dynamics simulations to X-ray crystallography
Jack B. Greisman, Lindsay Willmore, Christine Y. Yeh, Fabrizio Giordanetto, Sahar Shahamadtar, Hunter Nisonoff, Paul Maragakis, David E. Shaw
bioRxiv 2022.11.14.516467; doi: https://doi.org/10.1101/2022.11.14.516467

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