Accurate energy evaluation of receptor-ligand interaction

受体-配体相互作用的准确能量评估

• 批准号: 1846924
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1846924
• 关键词: Accurate; energy; evaluation; receptor; ligand

Drug design routinely uses existing computational methods to evaluate the interaction energy between receptor (protein) and ligand (drug) in molecular docking. The problem with these methods is that they are not reliable and accurate enough. One Perspective squarely asks "why docking remains so primitive that it is unable to even rank-order a hit list". A more realistic and accurate force field will make the so-called scoring functions that docking uses more reliable. Our lab has a deep knowledge of a next-generation in-house force field called FFLUX. This force field is much more realistic than a point-charge based force field such as AMBER. Moreover, FFLUX "sees the electrons" and is hence closer to the underlying quantum mechanics that ultimately governs the behaviour of all matter. FFLUX also introduces multipole moments, which is essential for accurate electrostatics.There is a modern and accurate energy partitioning method called Interacting Quantum Atoms (IQA), which offers a step change in the rigour of atomistic energy analysis. IQA is a parameter-free method that is intuitive but, at the same time, very close to the quantum mechanical character of atoms themselves. Originally rooted in small molecules, our lab has demonstrated that IQA can be now feasibly used for systems up to ~350 atoms. However, we have shown in work to be published that smaller systems (~150 atoms) suffice to obtain rigorous insight.Our in-house program ANANKE operates on a sequence of structures with varying distances and orientations of the receptor and ligand. ANANKE is able to highlight which fragments act like the total system, in terms of the various energetic contributions (both in type and locale). This is how, for the first time, a pharmacophore will be actually be computed.We aim to make this emerging technology available to AstraZeneca and work on case studies relevant to the company. This is an innovative project that aims to enhance long overdue realism and accuracy in drug design.

药物设计通常使用现有的计算方法来评估分子对接中受体（蛋白质）和配体（药物）之间的相互作用能。这些方法的问题在于它们不够可靠和准确。 《一个视角》直截了当地问“为什么对接仍然如此原始，甚至无法对命中列表进行排序”。更加真实和准确的力场将使对接所使用的所谓评分功能更加可靠。我们的实验室对名为 FFLUX 的下一代内部力场有着深入的了解。该力场比基于点电荷的力场（例如 AMBER）更加真实。此外，FFLUX“看到电子”，因此更接近最终控制所有物质行为的基础量子力学。 FFLUX 还引入了多极矩，这对于精确的静电学至关重要。有一种现代且精确的能量分配方法，称为相互作用量子原子 (IQA)，它使原子能量分析的严谨性发生了质的变化。 IQA 是一种无参数方法，非常直观，但同时非常接近原子本身的量子力学特征。我们的实验室最初植根于小分子，现已证明 IQA 现在可用于多达 350 个原子的系统。然而，我们在即将发表的工作中表明，较小的系统（约 150 个原子）足以获得严格的洞察力。我们的内部程序 ANANKE 对受体和配体的距离和方向不同的一系列结构进行操作。 ANANKE 能够突出显示哪些片段在各种能量贡献（类型和区域）方面与整个系统相似。这就是第一次实际计算药效团的方式。我们的目标是让阿斯利康能够使用这项新兴技术，并开展与该公司相关的案例研究。这是一个创新项目，旨在提高药物设计中早就应该的现实性和准确性。