SAR-Guided Scoring Function and Mutational Validation Reveal the Binding Mode of CGS-8216 at the α1+/γ2- Benzodiazepine Site

Journal of Chemical Information and Modeling
David C B SiebertGerhard F Ecker

Abstract

The structural resolution of a bound ligand-receptor complex is a key asset to efficiently drive lead optimization in drug design. However, structural resolution of many drug targets still remains a challenging endeavor. In the absence of structural knowledge, scientists resort to structure-activity relationships (SARs) to promote compound development. In this study, we incorporated ligand-based knowledge to formulate a docking scoring function that evaluates binding poses for their agreement with a known SAR. We showcased this protocol by identifying the binding mode of the pyrazoloquinolinone (PQ) CGS-8216 at the benzodiazepine binding site of the GABAA receptor. Further evaluation of the final pose by molecular dynamics and free energy simulations revealed a close proximity between the pendent phenyl ring of the PQ and γ2D56, congruent with the low potency of carboxyphenyl analogues. Ultimately, we introduced the γ2D56A mutation and in fact observed a 10-fold potency increase in the carboxyphenyl analogue, providing experimental evidence in favor of our binding hypothesis.

References

Aug 1, 1987·Molecular and Cellular Biology·C Chen, H Okayama
Jun 1, 1994·Proteins·M VihinenP Riikonen
Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Feb 1, 1995·Journal of Pharmacokinetics and Biopharmaceutics·Y HirschbergM Markowska
Apr 4, 1997·Journal of Molecular Biology·G JonesR Taylor
Aug 13, 2002·Current Topics in Medicinal Chemistry·Erwin Sigel
Aug 12, 2003·Proteins·Marcel L VerdonkRichard D Taylor
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Jan 26, 2005·Journal of Chemical Information and Modeling·Gerhard Wolber, Thierry Langer
Jan 18, 2006·Bioorganic & Medicinal Chemistry·Ramy FaridRobert A Pearlstein
Mar 3, 2007·Drug Discovery Today·Hanna Eckert, Jürgen Bajorath
Oct 2, 2007·Journal of Medicinal Chemistry·Lisa Peltason, Jürgen Bajorath
Mar 21, 2008·Journal of Computational Chemistry·Sunhwan JoWonpil Im
Jan 17, 2009·The Journal of Physical Chemistry. B·Yuqing Deng, Benoît Roux
Mar 26, 2009·Accounts of Chemical Research·William L Jorgensen
May 16, 2009·Journal of Computational Chemistry·B R BrooksM Karplus
Nov 26, 2009·Current Topics in Medicinal Chemistry·Aurijit Sarkar, Glen E Kellogg
Dec 1, 2010·Expert Opinion on Drug Discovery·Jessica Lynn Grey, David H Thompson
Jan 21, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Joachim RamerstorferMargot Ernst
Feb 26, 2011·Current Opinion in Structural Biology·John D ChoderaVijay S Pande
Apr 19, 2011·Journal of Computational Chemistry·Naveen Michaud-AgrawalOliver Beckstein
Jan 10, 2012·Methods in Molecular Biology·Shawn P Maddaford
May 9, 2012·Journal of Computer-aided Molecular Design·Christopher R CorbeilPaul Labute
Apr 1, 2010·Expert Opinion on Drug Discovery·Christian Beier, Martin Zacharias
Sep 18, 2012·Trends in Pharmacological Sciences·Phil Skolnick
Nov 14, 2012·Journal of Chemical Information and Modeling·K Vanommeslaeghe, A D MacKerell
Dec 4, 2012·Indian Journal of Pharmaceutical Sciences·V K VyasC Chintha
Jan 15, 2013·Journal of Chemical Theory and Computation·Peter EastmanVijay S Pande
Mar 28, 2013·Current Medicinal Chemistry·S F SousaM J Ramos
Jul 3, 2013·Journal of Chemical Information and Modeling·Denis FourchesAlexander Tropsha
Oct 15, 2013·Journal of Chemical Theory and Computation·Gregory A RossPhilip C Biggin

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