Computer simulation of mini-fragment binding in drug discovery

基于片段的药物发现（FBDD）在制药行业中越来越重要。筛选低分子量小分子（片段）文库以结合蛋白质靶标。虽然有许多实验途径（例如SPR，NMR）来评估结合，但通过X射线晶体学鉴定结合的片段浸入蛋白质晶体中可以说是最有效的。在鉴定了低分子量命中物之后，使用建立在蛋白质-配体晶体结构上的计算方法来建议对片段的化学修饰，以改善结合亲和力、对特定蛋白质靶标的特异性以及其他物理化学性质，例如溶解度。该项目的目的是利用小分子片段的实验结合数据来测试和指导计算机模拟方法的发展，以模拟片段结合。适当验证的计算机模拟方法的开发不仅可以指导实验，而且还可以用于不适合实验方法的情况，其中由于溶解度或聚集原因不可能存在高浓度配体，或者片段诱导蛋白质变性。传统的分子动力学可能会受到动力学障碍导致的采样不足的阻碍，即片段通过简单扩散结合受体所需的时间尺度太慢，以至于无法在微米长度的分子动力学模拟中建模。为了解决这一抽样限制，将采用增强的抽样模拟方法。

Fragment-based drug discovery (FBDD) is proving increasingly important in the pharmaceutical industry. A library of small molecules of low molecular weight (fragments) are screened for binding against a protein target. While there are a number of experimental routes (e.g. SPR, NMR) to assess binding, fragment soaking into protein crystals, with binding being identified through X-ray crystallography, is arguably the most effective. Having identified a low molecular weight hit, computational approaches that build on the protein-ligand crystal structure are used to suggest chemical modifications to the fragment to improve binding affinity, specificity to the specific protein target, and other physico-chemical properties such as solubility. The aim of this project is to use the experimental binding data of small molecular fragments to test and guide the development of computer simulation approaches to model fragment binding. The development of appropriately validated in silico methods will not only guide experiment, but can also be used in cases unsuited to the experimental approach, where high concentration of ligand is impossible for solubility or aggregation reasons, or where the fragments induce protein denaturation. Conventional molecular dynamics can be hampered by inadequate sampling due to kinetic barriers i.e. the timescales required for the fragments to bind the receptor by simple diffusion are too slow to be modelled in a micros-length molecular dynamics simulation. To address this sampling limitation, enhanced sampling simulation approaches will be employed.