Lewis Jana A, Lebois Evan P, Lindsley Craig W
Department of Pharmacology and Chemistry, Vanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232-6600, USA.
Curr Opin Chem Biol. 2008 Jun;12(3):269-80. doi: 10.1016/j.cbpa.2008.02.014. Epub 2008 Apr 18.
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.
与传统的正构结合位点不同，变构结合位点为药物发现提供了无与伦比的机会，它具有高度的选择性，能模拟生理条件，由于脱敏/下调作用副作用较少，并且能产生与正构配体化学类型不同的配体。对于激酶而言，迄今为止所描述的变构机制包括改变蛋白激酶构象以阻断有效的ATP结合（这看起来是“ATP竞争性的”），或者通过构象变化阻断激酶激活（这是“ATP非竞争性的”）。对于G蛋白偶联受体（GPCR），变构机制赋予了多种靶点调节模式（正变构调节（PAM）、负变构调节（NAM）、中性协同作用、部分拮抗作用（PA）、变构激动作用和变构拮抗作用）。在此，我们综述了激酶和GPCR变构配体的设计原则和结构多样性方面的最新进展。
