Incorporating protein flexibility in structure-based drug discovery: Using HIV-1 protease as a test case
Incorporating protein flexibility in structure-based drug discovery: Using HIV-1 protease as a test case
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DOI：
10.1021/ja0469378
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发表时间：
2004-10-20
影响因子：
15
通讯作者：
Carlson, HA
中科院分区：
文献类型：
--
作者：
Meagher, KL;Carlson, HA
我们开发了一种基于受体的药效团方法，该方法利用蛋白质结构的集合来解释基于结构的药物设计中固有的蛋白质灵活性。几个程序进行了系统的评估，以获得最通用的协议，使用多种蛋白质结构。最值得注意的是，引入更多的蛋白质灵活性改善了该方法的性能。药效团模型成功地区分已知的抑制剂从药物样非抑制剂。此外，该模型正确地识别了一些配体的结合构象。我们使用unliganded HIV-1蛋白酶来开发和验证这种方法。药物设计总是从蛋白质-配体结构开始，并且未结合蛋白质结构的这种成功是显著的-特别是在HIV-1蛋白酶的情况下，其在结合后具有大的构象变化。这种技术有望在结合晶体结构被发现之前成功地进行基于计算机的药物设计，这可能意味着用计算方法解决一些医学相关系统需要1-3年的时间。
We have developed a receptor-based pharmacophore method which utilizes a collection of protein structures to account for inherent protein flexibility in structure-based drug design. Several procedures were systematically evaluated to derive the most general protocol for using multiple protein structures. Most notably, incorporating more protein flexibility improved the performance of the method. The pharmacophore models successfully discriminate known inhibitors from drug-like non-inhibitors. Furthermore, the models correctly identify the bound conformations of some ligands. We used unliganded HIV-1 protease to develop and validate this method. Drug design is always initiated with a protein-ligand structure, and such success with unbound protein structures is remarkable - particularly in the case of HIV-1 protease, which has a large conformational change upon binding. This technique holds the promise of successful computer-based drug design before bound crystal structures are even discovered, which can mean a jump-start of 1-3 years in tackling some medically relevant systems with computational methods.