Integration of Enhanced Sampling Methods with Saturation Transfer Difference Experiments to Identify Protein Druggable Pockets

Journal of Chemical Information and Modeling
Joana MagalhãesGabriele Costantino

Abstract

Saturation transfer difference (STD) is an NMR technique conventionally applied in drug discovery to identify ligand moieties relevant for binding to protein cavities. This is important to direct medicinal chemistry efforts in small-molecule optimization processes. However, STD does not provide any structural details about the ligand-target complex under investigation. Herein, we report the application of a new integrated approach, which combines enhanced sampling methods with STD experiments, for the characterization of ligand-target complexes that are instrumental for drug design purposes. As an example, we have studied the interaction between StOASS-A, a potential antibacterial target, and an inhibitor previously reported. This approach allowed us to consider the ligand-target complex from a dynamic point of view, revealing the presence of an accessory subpocket which can be exploited to design novel StOASS-A inhibitors. As a proof of concept, a small library of derivatives was designed and evaluated in vitro, displaying the expected activity.

References

Apr 18, 2002·Proceedings of the National Academy of Sciences of the United States of America·Peter J WinnRebecca C Wade
Sep 25, 2002·Proceedings of the National Academy of Sciences of the United States of America·Alessandro Laio, Michele Parrinello
May 12, 2004·Magnetic Resonance in Chemistry : MRC·Yu-Sen WangDaniel F Wyss
Jan 8, 2009·Journal of Chemical Information and Modeling·Oliver KorbThomas E Exner
May 8, 2009·Journal of Computational Chemistry·M BonomiM Parrinello
Oct 2, 2009·Chemical Biology & Drug Design·Ernesto Freire
Nov 26, 2009·Journal of Medicinal Chemistry·Enea SalsiAndrea Mozzarelli
May 14, 2010·Journal of the American Chemical Society·Francesco ColizziAndrea Cavalli
Jul 6, 2010·Research in Microbiology·Amy L Turnbull, Michael G Surette
Jan 13, 2012·Proceedings of the National Academy of Sciences of the United States of America·Vittorio LimongelliMichele Parrinello
Jan 19, 2013·Journal of Chemical Theory and Computation·William L Jorgensen, Patric Schyman
Jan 22, 2013·Angewandte Chemie·Vittorio LimongelliMichele Parrinello
Apr 5, 2013·Proceedings of the National Academy of Sciences of the United States of America·Vittorio LimongelliMichele Parrinello
Jan 1, 2015·Journal of the American Chemical Society·Laura TroussicotJean-Marc Lancelin
Jan 15, 2015·European Journal of Medicinal Chemistry·Marco PieroniGabriele Costantino
Jan 22, 2015·Proceedings of the National Academy of Sciences of the United States of America·Pratyush TiwaryMichele Parrinello
Jan 26, 2016·Journal of Medicinal Chemistry·Marco De VivoAndrea Cavalli
Feb 24, 2016·Journal of Medicinal Chemistry·Matthew D SegallEdmund J Champness
Mar 17, 2016·Annual Review of Physical Chemistry·Omar ValssonMichele Parrinello
May 27, 2016·Journal of Chemical Theory and Computation·Federico ComitaniCarla Molteni
Jun 1, 2013·Molecular Informatics·Agostino BrunoGabriele Costantino
Nov 29, 2016·Drug Discovery Today·Aravindhan GanesanKhaled Barakat
Apr 18, 2017·Current Topics in Medicinal Chemistry·Gerard Martínez-RosellGianni de Fabritiis

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Citations

Sep 18, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Joana MagalhãesBarbara Campanini
Oct 5, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Giannamaria AnnunziatoGabriele Costantino
Oct 27, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Joana MagalhãesGabriele Costantino
Nov 27, 2019·International Journal of Molecular Sciences·Giannamaria Annunziato
Nov 15, 2020·Expert Opinion on Therapeutic Patents·Giannamaria Annunziato, Gabriele Costantino
May 22, 2020·ACS Medicinal Chemistry Letters·Joana MagalhãesGabriele Costantino

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