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。这些方法的问题在于它们不够可靠和准确。一个观点直接问“为什么对接仍然如此原始，它甚至不能排名排序的打击名单”。一个更真实和准确的力场将使对接使用的所谓评分功能更加可靠。我们的实验室对下一代内部力场FFLUX有着深入的了解。这种力场比基于点电荷的力场（如琥珀）更真实。此外，FFLUX“看到了电子”，因此更接近最终控制所有物质行为的基本量子力学。FFLUX还引入了多极矩，这对于精确的静电学是必不可少的。有一种称为相互作用量子原子（IQA）的现代精确能量划分方法，它为原子能量分析的严格性提供了一个步骤。IQA是一种直观的无参数方法，但同时非常接近原子本身的量子力学特性。最初植根于小分子，我们的实验室已经证明，IQA现在可以用于多达350个原子的系统。然而，我们已经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力。我们的内部程序ANANKE对受体和配体具有不同距离和方向的结构序列进行操作。ANANKE能够突出哪些片段像整个系统一样，在各种能量贡献方面（在类型和地点方面）。这是第一次，药效团将实际计算。我们的目标是使这一新兴技术提供给阿斯利康和工作的案例研究相关的公司。这是一个创新的项目，旨在提高药物设计的现实性和准确性。

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.