Supervised Molecular Dynamics (SuMD) as a Helpful Tool To Depict GPCR-Ligand Recognition Pathway in a Nanosecond Time Scale

Supervised MD (SuMD) is a computational method that allows the exploration of ligand-receptor recognition pathway investigations in a nanosecond (ns) time scale. It consists of the incorporation of a tabu-like supervision algorithm on the ligand-receptor approaching distance into a classic molecular dynamics (MD) simulation technique. In addition to speeding up the acquisition of the ligand-receptor trajectory, this implementation facilitates the characterization of multiple binding events (such as meta-binding, allosteric, and orthosteric sites) by taking advantage of the all-atom MD simulations accuracy of a GPCR-ligand complex embedded into explicit lipid-water environment.

[1]  G. de Fabritiis,et al.  Complete reconstruction of an enzyme-inhibitor binding process by molecular dynamics simulations , 2011, Proceedings of the National Academy of Sciences.

[2]  J. Wess,et al.  Site-directed Mutagenesis Identifies Residues Involved in Ligand Recognition in the Human A2a Adenosine Receptor (*) , 1995, The Journal of Biological Chemistry.

[3]  Albert C. Pan,et al.  Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs , 2013, Nature.

[4]  J. Drews.  Drug discovery: a historical perspective. , 2000, Science.

[5]  Adriaan P. IJzerman,et al.  The 2.6 A Crystal Structure of a Human A2A Adenosine Receptor bound to ZM241385. , 2008 .

[6]  J. Wess,et al.  Glutamate residues in the second extracellular loop of the human A2a adenosine receptor are required for ligand recognition. , 1996, Molecular pharmacology.

[7]  Albert C. Pan,et al.  Pathway and mechanism of drug binding to G-protein-coupled receptors , 2011, Proceedings of the National Academy of Sciences.

[8]  Jeff Wereszczynski,et al.  Comparison of Dynamics of Extracellular Accesses to the β1 and β2 Adrenoceptors Binding Sites Uncovers the Potential of Kinetic Basis of Antagonist Selectivity , 2012, Chemical biology & drug design.

[9]  A. Hopkins,et al.  The druggable genome , 2002, Nature Reviews Drug Discovery.

[10]  Ron O. Dror,et al.  Exploring atomic resolution physiology on a femtosecond to millisecond timescale using molecular dynamics simulations , 2010, The Journal of general physiology.

[11]  K. Jacobson,et al.  New Insights for Drug Design from the X-Ray Crystallographic Structures of G-Protein-Coupled Receptors , 2012, Molecular Pharmacology.

[12]  M. Congreve,et al.  Structure of the adenosine A(2A) receptor in complex with ZM241385 and the xanthines XAC and caffeine. , 2011, Structure.

[13]  Jonathan S. Mason,et al.  Discovery of 1,2,4-Triazine Derivatives as Adenosine A2A Antagonists using Structure Based Drug Design , 2012, Journal of medicinal chemistry.

[14]  S. Moro,et al.  Role of the extracellular loops of G protein-coupled receptors in ligand recognition: a molecular modeling study of the human P2Y1 receptor. , 1999, Biochemistry.