Computer simulation of mini-fragment binding in drug discovery

事实证明，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)的文库以与蛋白质靶标结合。虽然有许多实验途径(如SPR、核磁共振)来评估结合，但片段浸入蛋白质晶体中，结合通过X射线结晶学鉴定，可以说是最有效的。在确定了低分子量HIT后，基于蛋白质配体晶体结构的计算方法被用于建议对片段进行化学修饰，以提高与特定蛋白质靶标的结合亲和力、特异性和其他物理化学性质，如溶解性。本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。在计算机方法中适当验证的开发不仅将指导实验，而且还可以用于不适合实验方法的情况，其中由于溶解性或聚集原因不可能有高浓度的配体，或者片段导致蛋白质变性。由于动力学障碍，常规的分子动力学可能会受到采样不足的阻碍，即片段通过简单的扩散与受体结合所需的时间尺度太慢，无法在微米长的分子动力学模拟中建模。为了解决这一采样限制，将采用增强的采样模拟方法。

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.