Allosteric modulation of kinases and GPCRs: design principles and structural diversity.
Allosteric binding sites, as opposed to traditional orthosteric binding sites, offer unparalleled opportunities for drug discovery by providing high levels of selectivity, mimicking physiological conditions, affording fewer side effects because of desensitization/downregulation, and engendering ligands with chemotypes divergent from orthosteric ligands. For kinases, allosteric mechanisms described to date include alteration of protein kinase conformation blocking productive ATP binding which appear 'ATP competitive' or blocking kinase activation by conformational changes that are 'ATP non-competitive'. For GPCRs, allosteric mechanisms impart multiple modes of target modulation (positive allosteric modulation (PAM), negative allosteric modulation (NAM), neutral cooperativity, partial antagonism (PA), allosteric agonism and allosteric antagonism). Here, we review recent developments in the design principles and structural diversity of allosteric ligands for kinases and GPCRs.
Lewis
Jana A
JA
Department of Pharmacology and Chemistry, Vanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232-6600, USA. jana.a.lewis@vanderbilt.edu
Lebois
Evan P
EP
Lindsley
Craig W
CW
D000494:Allosteric Regulation; D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D010770:Phosphotransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D010770:Phosphotransferases