Christopoulos (2002) Allosteric binding sites on cell-surface receptors- Novel targets for drug discovery, Nature Drug Discovery 1,198-210.英文精品课件.pdfVIP

R E V I E W S ALLOSTERIC BINDING SITES ON CELL-SURFACE RECEPTORS: NOVEL TARGETS FOR DRUG DISCOVERY Arthur Christopoulos Cell-surface receptors are the targets for more than 60% of current drugs. Traditionally, optimizing the interaction of lead molecules with the binding site for the endogenous agonist (orthosteric site) has been viewed as the best means of achieving selectivity of action. However, recent developments have highlighted the fact that drugs can interact with binding sites on the receptor molecule that are distinct from the orthosteric site, known as allosteric sites. Allosteric modulators could offer several advantages over orthosteric ligands, including greater selectivity and saturability of their effect. ORTHOSTERIC SITE Many avenues of drug discovery have long been driven molecules towards the classic agonist binding site on the The endogenous agonist by the concept of the cell-surface receptor as a selective receptor as a means for obtaining selectivity of action. binding site on a receptor. This target for chemotherapeutic agents, an idea that was Throughout this review, this site will be referred to as domain is also recognized by first introduced by Paul Ehrlich just over a century ago1. the ORTHOSTERIC SITE. Designing drugs to target orthosteric classic competitive antagonists Early impetus also came from John N. Langley’s2 sites seems logical, given that the requisite high degree and inverse agonists. proposal that receptors