Mapping the druggable allosteric space of G-protein coupled receptors: a fragment-based molecular dynamics approach.

Chemical Biology & Drug Design
Anthony Ivetac, J Andrew McCammon

Abstract

To address the problem of specificity in G-protein coupled receptor (GPCR) drug discovery, there has been tremendous recent interest in allosteric drugs that bind at sites topographically distinct from the orthosteric site. Unfortunately, structure-based drug design of allosteric GPCR ligands has been frustrated by the paucity of structural data for allosteric binding sites, making a strong case for predictive computational methods. In this work, we map the surfaces of the beta1 (beta1AR) and beta2 (beta2AR) adrenergic receptor structures to detect a series of five potentially druggable allosteric sites. We employ the FTMAP algorithm to identify 'hot spots' with affinity for a variety of organic probe molecules corresponding to drug fragments. Our work is distinguished by an ensemble-based approach, whereby we map diverse receptor conformations taken from molecular dynamics (MD) simulations totaling approximately 0.5 micros. Our results reveal distinct pockets formed at both solvent-exposed and lipid-exposed cavities, which we interpret in light of experimental data and which may constitute novel targets for GPCR drug discovery. This mapping data can now serve to drive a combination of fragment-based and virtual screening appro...Continue Reading

References

Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Apr 16, 1998·Protein Science : a Publication of the Protein Society·L S CavesM Karplus
May 1, 1996·Nature Biotechnology·C Mattos, D Ringe
Jul 4, 1998·The Journal of Biological Chemistry·T H JiI Ji
Mar 1, 1985·Physical Review A: General Physics·W G Hoover
Sep 1, 1995·Physical Review. E, Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics·H Grubmüller
Jan 24, 2002·Nature·Howard A RockmanRobert J Lefkowitz
May 16, 2002·Journal of the American Chemical Society·Jung-Hsin LinJ Andrew McCammon
May 31, 2002·Pharmacological Reviews·Arthur Christopoulos, Terry Kenakin
Jul 18, 2002·Nature Reviews. Drug Discovery·Terry Kenakin
Jul 18, 2002·Nature Reviews. Drug Discovery·Arthur Christopoulos
Nov 1, 2002·The Journal of Biological Chemistry·Gayathri SwaminathBrian Kobilka
Jul 3, 2003·Nature Reviews. Drug Discovery·Simon J Teague
Oct 16, 2003·Current Opinion in Pharmacology·Lauren T May, Arthur Christopoulos
Mar 19, 2004·Nursing Standard·Beverly Malone
Mar 23, 2004·Nucleic Acids Research·Robert C Edgar
Apr 2, 2004·Journal of Medicinal Chemistry·Julie R SchamesJ Andrew McCammon
Jul 23, 2004·The Journal of Chemical Physics·Donald HamelbergJ Andrew McCammon
Aug 3, 2004·Nature Reviews. Drug Discovery·David C ReesRobin Carr
Sep 29, 2004·Drug Discovery Today·Willem SoudijnAd P IJzerman
Dec 8, 2004·Current Opinion in Structural Biology·Jeanne A Hardy, James A Wells
Feb 11, 2005·Bioinformatics·Alasdair T R Laurie, Richard M Jackson
Mar 5, 2005·Cellular and Molecular Life Sciences : CMLS·C R McCuddenF S Willard
Oct 8, 2005·Journal of Computational Chemistry·David Van Der SpoelHerman J C Berendsen
May 11, 2006·Chemical Reviews·Stewart A Adcock, J Andrew McCammon
May 13, 2006·FEMS Microbiology Ecology·Milagros ZaballosFrancisco Rodríguez-Valera
Jun 27, 2006·Nature Chemical Biology·Xiaojie YaoBrian Kobilka
Jun 29, 2006·The Journal of Pharmacology and Experimental Therapeutics·Jonathan D UrbanRichard B Mailman
Oct 3, 2006·Annual Review of Pharmacology and Toxicology·Lauren T MayArthur Christopoulos
Dec 2, 2006·Nature Reviews. Drug Discovery·John P OveringtonAndrew L Hopkins
Jan 26, 2007·Nature Reviews. Cancer·Robert T Dorsam, J Silvio Gutkind
Feb 20, 2007·Journal of Medicinal Chemistry·Melissa R LandonSandor Vajda
Jun 16, 2007·The Journal of Physical Chemistry. B·Siewert J MarrinkAlex H de Vries
Jul 17, 2007·Trends in Pharmacological Sciences·Thue W Schwartz, Birgitte Holst
Jul 17, 2007·Trends in Pharmacological Sciences·Brian K Kobilka, Xavier Deupi
Sep 21, 2007·Chemistry Central Journal·Martin WeiselGisbert Schneider
Oct 24, 2007·Nature·Søren G F RasmussenBrian K Kobilka

❮ Previous
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Citations

Mar 10, 2012·Proceedings of the National Academy of Sciences of the United States of America·Patrick WeinkamAndrej Sali
May 4, 2012·Journal of the Royal Society, Interface·Jennifer L LahtiRuss B Altman
Jun 1, 2012·International Journal of Peptides·Brian HallKeith K Parker
Nov 1, 2011·BMC Biology·Jacob D Durrant, J Andrew McCammon
Jan 28, 2014·PLoS Computational Biology·Zoltan PalmaiErika Balog
Apr 14, 2012·Journal of Biomedicine & Biotechnology·Marlet Martinez-ArchundiaJuan J Perez
Dec 18, 2013·Biophysical Chemistry·Ferran FeixasJ Andrew McCammon
Nov 28, 2012·Trends in Pharmacological Sciences·J Robert LaneArthur Christopoulos
Jun 26, 2012·Pharmacology & Therapeutics·Christa E MüllerYounis Baqi
Jul 17, 2014·Biophysical Journal·Supriyo Bhattacharya, Nagarajan Vaidehi
Oct 12, 2013·Chemical Biology & Drug Design·Yinglong MiaoJ Andrew McCammon
Apr 14, 2016·Chemical Reviews·Jeffrey R WagnerRommie E Amaro
Dec 4, 2012·Biophysical Journal·Christian Seifert, Frauke Gräter
Feb 13, 2016·Chemical Biology & Drug Design·Wei ZhangYonghe Li
Oct 26, 2016·Protein Science : a Publication of the Protein Society·Aneesh Chandran, Saraswathi Vishveshwara
Jul 18, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Damian BartuziDariusz Matosiuk
Oct 3, 2019·Protein Science : a Publication of the Protein Society·Ji Young LeeIvet Bahar
Mar 1, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Damian BartuziDariusz Matosiuk
Mar 6, 2019·Current Pharmaceutical Design·Mohammed Nooraldeen Mahmod Al-Qattan, Mohd Nizam Mordi
Apr 18, 2019·Scientific Reports·Amanda E WakefieldGyörgy M Keserű
Jan 13, 2021·International Journal of Molecular Sciences·Serena VittorioLaura De Luca
Jun 24, 2017·Chemical Biology & Drug Design·Alisha D CalimanJames A McCammon
May 4, 2011·Journal of Chemical Information and Modeling·Sara E NicholsJ Andrew McCammon
Jun 10, 2014·Journal of Chemical Information and Modeling·Yaw Sing TanChandra Verma
May 13, 2014·Journal of Chemical Theory and Computation·Teresa ParamoPeter J Bond
Jul 17, 2012·Journal of Chemical Theory and Computation·Ahmet BakanIvet Bahar
Feb 20, 2018·Journal of Medicinal Chemistry·Shaoyong Lu, Jian Zhang
Apr 1, 2015·Future Medicinal Chemistry·David R Hall, Istvan J Enyedy

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Methods Mentioned

BETA
X-ray
NMR

Software Mentioned

FTMAP
GROMOS
MODELLER
Visual Molecular Dynamics ( VMD )
MUSCLE
GROMOS96
GROMACS
CS
Map

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