Exploring Cryptic Pockets Formation in Targets of Pharmaceutical Interest with SWISH

Journal of Chemical Theory and Computation
Federico Comitani, Francesco L Gervasio

Abstract

Cryptic (hidden) pockets are sites that are not visible on unliganded target proteins' structures and only become apparent when a ligand binds. They might provide a valid alternative to classical binding sites in otherwise "undruggable" targets, but their hidden nature makes it difficult to use standard structure-based or computer-aided drug discovery approaches. Our group recently developed a Hamiltonian replica-exchange method (sampling water interfaces through scaled Hamiltonians or SWISH) that improves the sampling of hydrophobic cavities by scaling the interactions between water molecules and protein atoms. Here, we discuss further improvements to SWISH and its combination with fragment probe simulations. We tested the robustness and general applicability of the improved approach in a variety of pharmaceutically relevant targets. The chosen proteins: NPC2, p38α, LfrR, and hPNMT, represent a set of diversified and interesting targets harboring nontrivial cryptic binding sites. In all cases, the updated version of our algorithm efficiently explored the cryptic sites.

References

Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Aug 16, 2000·Proceedings of the National Academy of Sciences of the United States of America·D A ErlansonJ A Wells
Sep 5, 2002·Nature Reviews. Drug Discovery·Andrew L Hopkins, Colin R Groom
Sep 25, 2002·Proceedings of the National Academy of Sciences of the United States of America·Alessandro Laio, Michele Parrinello
Feb 20, 2003·Proceedings of the National Academy of Sciences of the United States of America·Natalia FriedlandAnn M Stock
Apr 26, 2003·The Journal of Investigative Dermatology·Richard L EckertShervin Dashti
Jul 2, 2003·Current Opinion in Structural Biology·Stephen J CampbellDavid R Westhead
May 1, 1965·Journal of Molecular Biology·J MONODJ P CHANGEUX
Nov 25, 2003·Nature Structural Biology·Helen BermanHaruki Nakamura
Mar 24, 2004·Journal of Molecular Biology·James R Horn, Brian K Shoichet
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Oct 18, 2006·Antimicrobial Agents and Chemotherapy·Silvia BuroniEdda De Rossi
Jan 11, 2007·The Journal of Chemical Physics·Giovanni BussiMichele Parrinello
Jun 19, 2007·The Journal of Biological Chemistry·Sujuan XuAnn M Stock
Sep 12, 2007·Journal of Medicinal Chemistry·Christine L GeeJennifer L Martin
Nov 15, 2007·Journal of Molecular Biology·Ron DiskinOded Livnah
Dec 14, 2007·Nature·James A Wells, Christopher L McClendon
Jan 10, 2009·Nature Protocols·Lorenza BordoliTorsten Schwede
Mar 20, 2009·Journal of Medicinal Chemistry·Jesus SecoXavier Barril
Jul 14, 2009·PLoS Computational Biology·Olgun Guvench, Alexander D MacKerell
Oct 13, 2009·Journal of Bacteriology·Marco BellinzoniPedro M Alzari
Jun 15, 2010·Trends in Biochemical Sciences·Peter CsermelyRuth Nussinov
Aug 6, 2010·Journal of Medicinal Chemistry·Peter Schmidtke, Xavier Barril
Dec 17, 2010·Journal of the American Chemical Society·Katrina W Lexa, Heather A Carlson
Jul 4, 2012·Proceedings of the National Academy of Sciences of the United States of America·Gregory R Bowman, Phillip L Geissler
Jul 17, 2012·Journal of Chemical Theory and Computation·Ahmet BakanIvet Bahar
Oct 20, 2012·Journal of Molecular Biology·Netanel TzarumOded Livnah
Jun 12, 2013·Proceedings of the National Academy of Sciences of the United States of America·Ludovico Sutto, Francesco Luigi Gervasio
Oct 12, 2013·Annual Review of Pharmacology and Toxicology·Cody J WenthurCraig W Lindsley
Dec 17, 2014·Bioinformatics·Benoist LaurentMarc Baaden
Feb 24, 2015·PLoS Computational Biology·David K Johnson, John Karanicolas
Apr 14, 2015·Journal of the American Chemical Society·Kristen A MarinoFrancesco Luigi Gervasio
Sep 18, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Benjamin P Cossins, Alastair D G Lawson
Oct 22, 2015·Biophysical Journal·Robert T McGibbonVijay S Pande
Nov 18, 2015·Journal of Chemical Theory and Computation·James A MaierCarlos Simmerling
Nov 19, 2015·Journal of Chemical Theory and Computation·Rémi CuchilloJulien Michel
Sep 9, 2014·Journal of Chemical Theory and Computation·Elena PapaleoKresten Lindorff-Larsen
Nov 26, 2015·PLoS Computational Biology·Silvia LoveraFrancesco L Gervasio
Oct 13, 2009·Journal of Chemical Theory and Computation·Willy WriggersDavid E Shaw
Dec 15, 2015·Proceedings of the National Academy of Sciences of the United States of America·R Frederick LudlowHarren Jhoti
Feb 9, 2016·Journal of Molecular Biology·Peter CimermancicAndrej Sali

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Citations

Sep 7, 2019·International Journal of Molecular Sciences·Luca Pinzi, Giulio Rastelli
Dec 14, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lucas A DefelipeXavier Barril
Jun 30, 2019·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Haoqi WangSandun Fernando
Sep 5, 2020·International Journal of Molecular Sciences·Raudah LazimSun Choi
Dec 22, 2020·Frontiers in Molecular Biosciences·Irène PitardThérèse E Malliavin
Feb 12, 2021·Journal of Chemical Information and Modeling·Harsh BansiaSuryanarayanarao Ramakumar
Jun 8, 2021·Journal of Chemical Information and Modeling·Daniel J EvansAlbert Y Lau
Jul 1, 2021·Journal of Chemical Theory and Computation·Monika MichaelisLucio Colombi Ciacchi
Mar 17, 2020·Journal of Chemical Information and Modeling·Gerard Martinez-RosellGianni De Fabritiis
Mar 7, 2020·Accounts of Chemical Research·Antonija KuzmanicFrancesco L Gervasio
Nov 21, 2021·Proceedings of the National Academy of Sciences of the United States of America·Catherine R KnoverekGregory R Bowman
Dec 23, 2021·Expert Opinion on Drug Discovery·Ashfaq Ur RehmanJian Zhang

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