Using the fragment molecular orbital method to investigate agonist-orexin-2 receptor interactions.
Using the fragment molecular orbital method to investigate agonist-orexin-2 receptor interactions.
复制标题
使用碎片分子轨道方法研究激动剂 - 蛋白质-2受体相互作用。
DOI：
10.1042/bst20150250
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发表时间：
2016-04-15
影响因子：
3.9
通讯作者：
Biggin PC
中科院分区：
文献类型：
--
作者：
Heifetz A;Aldeghi M;Chudyk EI;Fedorov DG;Bodkin MJ;Biggin PC
了解任何蛋白质与小分子之间的结合作用对亲和力和选择性的合理化起着关键作用，对于高效的基于结构的药物发现(SBDD)过程是必不可少的。显然，要开始SBDD，需要一个结构，尽管在解决G蛋白偶联受体(GPCR)晶体结构方面已经取得了惊人的进展，但这个过程仍然相当缓慢，目前并不适用于每一个GPCR或GPCR-配体复合体。这种情况极大地限制了X射线结晶学“实时”影响GPCR靶的药物发现过程的能力，因此仍然需要其他实用和成本效益高的替代方案。我们在这里提出了一种方法，它集成了我们之前描述的分层GPCR建模协议(HGMP)和片段分子轨道(FMO)量子力学(QM)方法来探索人增食欲素-2受体(OX2R)及其最近发现的非肽激动剂的相互作用和选择性。HGMP通过应用一组计算方法生成了GPCR结构及其与小分子的络合物的3D模型。FMO允许从头开始的方法应用于传统的质量管理方法会发现具有挑战性的系统。FMO的主要优点是它可以揭示每个残基和水分子对配体结合的个别贡献和化学性质的信息，而没有QM通常很难检测到这些信息。我们说明了这两种技术的结合如何提供了一种实用而有效的方法，可以用于分析现有的结构-功能关系(SAR)，并在一个真实世界的例子中推动SBDD，对于这个例子，没有可用的络合物的晶体结构。
The understanding of binding interactions between any protein and a small molecule plays a key role in the rationalization of affinity and selectivity and is essential for an efficient structure-based drug discovery (SBDD) process. Clearly, to begin SBDD, a structure is needed, and although there has been fantastic progress in solving G-protein-coupled receptor (GPCR) crystal structures, the process remains quite slow and is not currently feasible for every GPCR or GPCR–ligand complex. This situation significantly limits the ability of X-ray crystallography to impact the drug discovery process for GPCR targets in ‘real-time’ and hence there is still a need for other practical and cost-efficient alternatives. We present here an approach that integrates our previously described hierarchical GPCR modelling protocol (HGMP) and the fragment molecular orbital (FMO) quantum mechanics (QM) method to explore the interactions and selectivity of the human orexin-2 receptor (OX2R) and its recently discovered nonpeptidic agonists. HGMP generates a 3D model of GPCR structures and its complexes with small molecules by applying a set of computational methods. FMO allows ab initio approaches to be applied to systems that conventional QM methods would find challenging. The key advantage of FMO is that it can reveal information on the individual contribution and chemical nature of each residue and water molecule to the ligand binding that normally would be difficult to detect without QM. We illustrate how the combination of both techniques provides a practical and efficient approach that can be used to analyse the existing structure–function relationships (SAR) and to drive forward SBDD in a real-world example for which there is no crystal structure of the complex available.