Accurate energy evaluation of receptor-ligand interaction

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。这些方法的问题是它们不够可靠和准确。One透视直截了当地问道：“为什么停靠仍然如此原始，以至于它甚至无法对暗杀名单进行排名。”一个更真实、更准确的力场将使对接使用的所谓计分功能更加可靠。我们的实验室对名为FFLUX的下一代内部力场有深入的了解。该力场比基于点电荷的力场(如琥珀)更逼真。此外，FFLUX“看到了电子”，因此更接近于最终决定所有物质行为的基本量子力学。FFLUX还引入了多极矩，这对于精确的静电是必不可少的。有一种称为相互作用量子原子(IQA)的现代精确能量分配方法，它使原子能量分析的严谨性发生了阶段性变化。IQA是一种无参数的方法，它直观，但同时非常接近原子本身的量子力学特征。最初植根于小分子，我们的实验室已经证明，IQA现在可以可行地用于高达~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(~150个原子)足以获得严格的洞察。我们的内部程序ANANKE对受体和配体的不同距离和取向的结构序列进行操作。ANANKE能够根据不同的能量贡献(类型和地点)来强调哪些碎片的行为类似于整个系统。这将是第一次实际计算药效团的方法。我们的目标是使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。这是一个创新的项目，旨在提高药物设计中期待已久的现实性和准确性。

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.