Supporting the Identification of Novel Fragment-Based Positive Allosteric Modulators Using a Supervised Molecular Dynamics Approach: A Retrospective Analysis Considering the Human A2A Adenosine Receptor as a Key Example

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Giuseppe Deganutti, Stefano Moro

Abstract

Structure-driven fragment-based (SDFB) approaches have provided efficient methods for the identification of novel drug candidates. This strategy has been largely applied in discovering several pharmacological ligand classes, including enzyme inhibitors, receptor antagonists and, more recently, also allosteric (positive and negative) modulators. Recently, Siegal and collaborators reported an interesting study, performed on a detergent-solubilized StaR adenosine A2A receptor, describing the existence of both fragment-like negative allosteric modulators (NAMs), and fragment-like positive allosteric modulators (PAMs). From this retrospective study, our results suggest that Supervised Molecular Dynamics (SuMD) simulations can support, on a reasonable time scale, the identification of fragment-like PAMs following their receptor recognition pathways and characterizing the possible allosteric binding sites.

References

Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Sep 25, 2002·Proceedings of the National Academy of Sciences of the United States of America·Alessandro Laio, Michele Parrinello
Oct 31, 2003·Journal of Medicinal Chemistry·Soo-Kyung KimKenneth A Jacobson
Oct 8, 2005·Journal of Computational Chemistry·David Van Der SpoelHerman J C Berendsen
Jan 7, 2006·Bioinformatics·Mikhail A LomizeHenry I Mosberg
Jan 11, 2007·The Journal of Chemical Physics·Giovanni BussiMichele Parrinello
Feb 1, 2008·Physical Review Letters·Alessandro BarducciMichele Parrinello
Mar 26, 2010·Journal of Computational Chemistry·Maarten G WolfGerrit Groenhof
Oct 29, 2010·Methods in Molecular Biology·Eric FeyfantDésirée H H Tsao
Jul 17, 2012·Science·Wei LiuRaymond C Stevens
Nov 14, 2012·Journal of Chemical Information and Modeling·K VanommeslaegheA D MacKerell
Nov 14, 2012·Journal of Chemical Information and Modeling·K Vanommeslaeghe, A D MacKerell
Jul 9, 2013·Journal of Computational Chemistry·Jing Huang, Alexander D MacKerell
Dec 3, 2013·Nucleic Acids Research·Zhimin HuangJian Zhang
Jan 15, 2014·Progress in Medicinal Chemistry·Miles CongreveFiona H Marshall
Jan 25, 2014·Journal of Chemical Information and Modeling·Davide Sabbadin, Stefano Moro
Apr 8, 2014·The Journal of Physical Chemistry. B·Karl T DebiecLillian T Chong
Dec 5, 2014·Molecular Pharmacology·Arnault MassinkAdriaan P IJzerman
Jun 24, 2015·The Journal of Biological Chemistry·Ali JazayeriFiona H Marshall
Sep 2, 2015·Current Topics in Medicinal Chemistry·Catherine F LathamGilda Tachedjian
Sep 15, 2015·Nucleic Acids Research·Qiancheng ShenJian Zhang
Nov 6, 2015·Trends in Pharmacological Sciences·Antonella CiancettaStefano Moro
Jun 9, 2009·Journal of Chemical Theory and Computation·M J HarveyG De Fabritiis
Mar 29, 2016·Journal of Chemical Information and Modeling·Alberto CuzzolinStefano Moro
Jul 28, 2016·Nature·Byron CarpenterChristopher G Tate
Aug 6, 2016·Molecular Informatics·Noelia Ferruz, Gianni De Fabritiis
Feb 9, 2017·Proceedings of the National Academy of Sciences of the United States of America·Bingfa SunBrian K Kobilka
Apr 1, 2017·Future Medicinal Chemistry·Giuseppe Deganutti, Stefano Moro

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Citations

Mar 6, 2019·Current Pharmaceutical Design·Mohammed Nooraldeen Mahmod Al-Qattan, Mohd Nizam Mordi
Mar 6, 2019·Current Pharmaceutical Design·Nizar A Al-Shar'i, Qosay A Al-Balas
Jul 21, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Francisco Ciruela, Eddy Sotelo
Mar 30, 2021·Journal of Chemical Information and Modeling·Giuseppe DeganuttiChristopher A Reynolds
Dec 24, 2020·Expert Opinion on Drug Discovery·Julio Caballero
Mar 4, 2020·Journal of Chemical Information and Modeling·Giuseppe DeganuttiChristopher A Reynolds
Sep 14, 2021·Frontiers in Molecular Biosciences·Giuseppe DeganuttiChristopher A Reynolds

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Methods Mentioned

BETA
X-ray

Software Mentioned

membed
MOE
CHARMM
CGenFF
SuMD
- 3D
Solvate1
Gaussian
PLUMED
Paramchem

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