Allosteric modulation of kinases and GPCRs: design principles and structural diversity.

Lewis JA, Lebois EP, Lindsley CW
Curr Opin Chem Biol. 2008 12 (3): 269-80

PMID: 18342020 · DOI:10.1016/j.cbpa.2008.02.014

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.

MeSH Terms (8)

Allosteric Regulation Animals Drug Design Enzyme Inhibitors Humans Ligands Phosphotransferases Receptors, G-Protein-Coupled

Connections (2)

This publication is referenced by other Labnodes entities: