Alberts Ian L, Todorov Nikolay P, Dean Philip M
De Novo Pharmaceuticals, Compass House, Vision Park, Histon, Cambridge CB4 9ZR, U.K.
J Med Chem. 2005 Oct 20;48(21):6585-96. doi: 10.1021/jm050196j.
One of the major problems in computational drug design is incorporation of the intrinsic flexibility of protein binding sites. This is particularly crucial in ligand binding events, when induced fit can lead to protein structure rearrangements. As a consequence of the huge conformational space available to protein structures, receptor flexibility is rarely considered in ligand design procedures. In this work, we present an algorithm for integrating protein binding-site flexibility into de novo ligand design and docking processes. The approach allows dynamic rearrangement of amino acid side chains during the docking and design simulations. The impact of protein conformational flexibility is investigated in the docking of highly active inhibitors in the binding sites of acetylcholinesterase and human collagenase (matrix metalloproteinase-1) and in the design of ligands in the S1' pocket of MMP-1. The results of corresponding simulations for both rigid and flexible binding sites are compared in order to gauge the influence of receptor flexibility in drug discovery protocols.
计算药物设计中的一个主要问题是如何纳入蛋白质结合位点的内在灵活性。这在配体结合事件中尤为关键，因为诱导契合可能导致蛋白质结构重排。由于蛋白质结构具有巨大的构象空间，在配体设计过程中很少考虑受体的灵活性。在这项工作中，我们提出了一种将蛋白质结合位点灵活性整合到从头配体设计和对接过程中的算法。该方法允许在对接和设计模拟过程中动态重排氨基酸侧链。通过对接乙酰胆碱酯酶和人胶原酶（基质金属蛋白酶-1）结合位点的高活性抑制剂以及设计MMP-1的S1'口袋中的配体，研究了蛋白质构象灵活性的影响。比较了刚性和柔性结合位点相应模拟的结果，以评估受体灵活性在药物发现方案中的影响。
