Cheminformatics Analysis of Dynamic WNK-Inhibitor Interactions

Molecular Informatics
Melaine A Kuenemann, Denis Fourches

Abstract

The With-No-Lysine (WNK) serine/threonine kinase family constitutes a unique and distinctive branch of the kinome. The four proteins of this family (WNK1/2/3/4) are involved in blood pressure regulation, body fluid, and electrolyte homeostasis. Herein, we modeled and analyzed the binding modes of all publicly-available small orthosteric and allosteric binders (including WNK463 and WNK467) experimentally tested towards any of the WNK family member. To do so, we relied on state-of-the-art cheminformatics approaches including structure-based molecular docking and molecular dynamics simulations. In particular, we computed and analyzed the (i) molecular selectivity of known inhibitors when docked in the binding site of each WNK family member, (ii) the dynamic WNK-inhibitor interactions at both orthosteric and allosteric sites to derive new structure-activity relationships, and (iii) the key specific interactions present in each binding site. This study reports on the first, cheminformatics-powered analysis of the entire chemical space of known WNK inhibitors. We discuss the conservation of critical WNK-inhibitor interactions and the existence of isoform-specific interactions that could enable the rational design of more potent and s...Continue Reading

References

Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Aug 11, 2001·Science·F H WilsonR P Lifton
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Mar 28, 2006·Journal of Chemical Information and Modeling·Chidochangu P MpamhangaPeter Willett
Sep 26, 2006·American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation·Gregory Proctor, Stuart Linas
Jan 24, 2007·Journal of Chemical Information and Modeling·Gilles Marcou, Didier Rognan
Feb 3, 2009·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Ewout J HoornRobert Zietse
Apr 15, 2009·Journal of Chemical Information and Modeling·Violeta I Pérez-NuenoJordi Teixidó
Apr 29, 2009·Journal of Computational Chemistry·Garrett M MorrisArthur J Olson
Aug 21, 2009·Bioorganic & Medicinal Chemistry·Stefan TaslerChristoph Schächtele
May 15, 2010·Bioorganic & Medicinal Chemistry·Delphine Lamoral-TheysJacques Dubois
Jun 25, 2010·Journal of Chemical Information and Modeling·Denis FourchesAlexander Tropsha
Jan 21, 2011·Physiological Reviews·James A McCormick, David H Ellison
Mar 26, 2011·Journal of the American Society of Nephrology : JASN·Ewout J HoornDavid H Ellison
Oct 13, 2011·Molecular Systems Biology·Fabian SieversDesmond G Higgins
Mar 13, 2012·Experimental Cell Research·Ewout J Hoorn, David H Ellison
Apr 11, 2013·Bioorganic & Medicinal Chemistry Letters·Srinivasa KarraSamantha Goodstal
Nov 12, 2013·Nucleic Acids Research·A Patrícia BentoJohn P Overington
May 8, 2014·Science Signaling·Alexander T PialaElizabeth J Goldsmith
Apr 10, 2015·Nucleic Acids Research·Céline M LabbéMaria A Miteva
Jul 15, 2015·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Eisei Sohara, Shinichi Uchida
Jul 22, 2015·Nature Chemical Biology·Denis FourchesAlexander Tropsha
Jun 10, 2016·Journal of Chemical Information and Modeling·Denis FourchesAlexander Tropsha
Oct 19, 2016·Nature Chemical Biology·Ken YamadaLauren Monovich
Oct 8, 2016·ACS Chemical Biology·Ken YamadaHyi-Man Park

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