Abstract:
: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.
journal_name
Curr Opin Chem Bioljournal_title
Current opinion in chemical biologyauthors
Lewis JA,Lebois EP,Lindsley CWdoi
10.1016/j.cbpa.2008.02.014subject
Has Abstractpub_date
2008-06-01 00:00:00pages
269-80issue
3eissn
1367-5931issn
1879-0402pii
S1367-5931(08)00035-5journal_volume
12pub_type
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