蛋白别构机制及其在药物研发中的展望

Allosteric Regulation:Mechanism Study and Applications in Drug Discovery

别构调节(allosteric regulation)是指调节分子结合在正位活性位点(orthosteric site)以外的位点,诱导蛋白构象变化来调节蛋白活性位点功能。别构调节具有位点多样化、调节分子多元化、调节特异性高和调节效应有上限等优点,使其成为新兴药物开发的重要策略。已有很多研究人员针对现有靶点研发别构药物,与以往正位活性位点的竞争性药物相比,别构药物特异性更好,能够区分家族内的同源蛋白,副作用小,并且实现从别构位点至活性位点的远程通讯,能够和内源性配体同时结合靶蛋白协同发挥功能等优点。该文将从别构调节的发展历史、机制、研究方法、别构调节剂的研究进展及别构药物开发的未来展望作一简要综述。

Allosteric regulation is that allosteric modulator binds at an allosteric site, a site distinct from the orthosteric site, inducing the change in conformation of protein to regulate its function activity. Allosteric regulation has many advantages due to specific features of allosteric sites, including structural diversity and flexibility. Then allosteric modulators show high selectivity, low toxicity and a ceiling effect on target, which presents a novel approach to drug discovery. In addition, allosteric modulator is able to trigger the communication between their binding allosteric site and corresponding functional site, as well as act in synergy with cofactors or endogenous ligands. This review focuses on the history, mechanism, methods of allostery, the progress of allosteric modulators and the outlook of allosteric drugs in drug discovery.