title: Unraveling structural mechanisms of allosteric drug action.
abstract: Orthosteric drugs block the active site to obstruct function; allosteric drugs modify the population of the active state, to modulate function. Available data lead us to propose that allosteric drugs can constitute anchors and drivers. The anchor docks into an allosteric pocket. The conformation with which it interacts is unchanged during the transition between the inactive and active states. The anchor provides the foundation that allows the driver to exert a 'pull' and/or 'push' action that shifts the receptor population from the inactive to the active state. The presence or absence of driver atom in an allosteric drug can exert opposite agonism. We map a strategy for driver identification and expect the allosteric trigger concept to transform agonist/antagonist drug discovery.
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: NussinoR@helix.nih.gov.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Chung-Jung
authors.initials: CJ
authors.lastname: Tsai
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D020134:Catalytic Domain / Q000187:drug effects; D055808:Drug Discovery; D008956:Models, Chemical; D008968:Molecular Conformation; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010600:Pharmacology / Q000379:methods; D013816:Thermodynamics
chemical_list: D004364:Pharmaceutical Preparations
keywords: agonist; allosteric drug discovery; allostery; anchor atom; antagonist; driver atom; protocol