Docking and binding free energy calculations of sirtuin inhibitors

European Journal of Medicinal Chemistry
Berin Karaman, Wolfgang Sippl

Abstract

Sirtuins form a unique and highly conserved class of NAD(+)-dependent lysine deacylases. Among these the human subtypes Sirt1-3 has been implicated in the pathogenesis of numerous diseases such as cancer, metabolic syndromes, viral diseases and neurological disorders. Most of the sirtuin inhibitors that have been identified so far show limited potency and/or isoform selectivity. Here, we introduce a promising method to generate protein-inhibitor complexes of human Sirt1, Sirt2 and Sirt3 by means of ligand docking and molecular dynamics simulations. This method highly reduces the complexity of such applications and can be applied to other protein targets beside sirtuins. To the best of our knowledge, we present the first binding free energy method developed by using a validated data set of sirtuin inhibitors, where both a fair number of compounds (33 thieno[3,2-d]pyrimidine-6-carboxamide derivatives) was developed and tested in the same laboratory and also crystal structures in complex with the enzyme have been reported. A significant correlation between binding free energies derived from MM-GBSA calculations and in vitro data was found for all three sirtuin subtypes. The developed MM-GBSA protocol is computationally inexpensive...Continue Reading

References

Mar 1, 1994·Protein Engineering·J AqvistJ E Samuelsson
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Oct 24, 2002·Journal of Computational Chemistry·Araz JakalianChristopher I Bayly
Jan 10, 2003·Nucleic Acids Research·Tamotsu Noguchi, Yutaka Akiyama
Sep 10, 2003·Biochemical and Biophysical Research Communications·Masaharu HiratsukaMitsuo Oshimura
Jan 30, 2004·Journal of the American Chemical Society·Kaushik Raha, Kenneth M Merz
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Mar 19, 2004·Journal of Medicinal Chemistry·Thomas A HalgrenJay L Banks
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Feb 19, 2005·PLoS Biology·Sara PagansMelanie Ott
Jun 10, 2005·Journal of Medicinal Chemistry·Bernd KuhnMartin Stahl
Dec 13, 2005·Journal of Medicinal Chemistry·Andrew D NapperRory Curtis
Jan 20, 2006·Journal of Medicinal Chemistry·Woody ShermanRamy Farid
Sep 29, 2006·Journal of Medicinal Chemistry·Gregory L WarrenMartha S Head
Jan 5, 2007·Annual Review of Biophysics and Biomolecular Structure·Michael K Gilson, Huan-Xiang Zhou
Jun 26, 2007·Science·Tiago Fleming OuteiroAleksey G Kazantsev
Aug 24, 2007·The Journal of Biological Chemistry·Nidhi AhujaEric Verdin
Nov 27, 2007·British Journal of Pharmacology·N MoitessierC R Corbeil
May 10, 2008·Journal of Chemical Information and Modeling·David C ThompsonDiane Joseph-McCarthy
Nov 4, 2008·European Journal of Medicinal Chemistry·Kanin WichapongWolfgang Sippl
Nov 21, 2007·Physical Chemistry Chemical Physics : PCCP·Landry CharlierJérome Golebiowski
Jul 2, 2009·Journal of Computational Chemistry·Giulio RastelliMiriam Sgobba
Dec 17, 2009·European Journal of Cell Biology·Kai Harting, Bernd Knöll
Feb 18, 2010·Journal of Chemical Theory and Computation·Roger S ArmenCharles L Brooks
Jul 6, 2010·Biochimica Et Biophysica Acta·Michael LawsonWolfgang Sippl
Aug 18, 2010·Journal of Chemical Information and Modeling·Kanin WichapongWolfgang Sippl
Jan 1, 2007·Journal of Chemical Theory and Computation·John MonganAlexey Onufriev
Jan 12, 2011·Journal of Chemical Theory and Computation·Seth A HayikKenneth M Merz
Feb 12, 2011·Journal of Chemical Information and Modeling·Anton LindströmAnna Linusson
Mar 2, 2011·Journal of Molecular Recognition : JMR·Elizabeth YurievPaul A Ramsland
Mar 3, 2011·The Journal of Biological Chemistry·Patricia W PanJohn M Denu
Apr 8, 2011·Cancer·Turki Y AlhazzaziYvonne L Kapila
Sep 21, 2011·Progress in Neurobiology·Feng ZhangJun Chen
Nov 1, 2011·BMC Biology·Jacob D Durrant, J Andrew McCammon

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Citations

Jan 23, 2016·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Lionel SacconnayAlessandra Nurisso
Jun 4, 2016·Journal of Molecular Graphics & Modelling·Wilian Augusto CortopassiRobert S Paton
Feb 10, 2017·Scientific Reports·Tarsis Ferreira GesteiraWinston W-Y Kao
Jan 18, 2017·Medicinal Research Reviews·Matthias SchiedelManfred Jung
Jan 26, 2018·Frontiers in Molecular Biosciences·Changhao WangRay Luo
Apr 15, 2020·International Journal of Molecular Sciences·Shuang ZhaoHui-Yu Li
Nov 6, 2018·European Journal of Medicinal Chemistry·Abdulkarim NajjarMatthias Schmidt
Oct 3, 2020·Chemical Reviews·Sergio Decherchi, Andrea Cavalli
Jun 19, 2021·Interdisciplinary Sciences, Computational Life Sciences·Li ChenQingjie Zhao
Aug 29, 2019·Journal of Chemical Information and Modeling·Eko Aditya RifaiDaan P Geerke
Sep 29, 2021·Journal of Biochemical and Molecular Toxicology·Rahagir SalekeenKazi Mohammed Didarul Islam

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