Free energy calculations in drug discovery

药物发现中的自由能计算

• 批准号: 2284197
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2284197
• 关键词: Free; energy; calculations; drug; discovery

Protein-ligand binding free energy is a crucial property used in the discovery and optimisation of novel drugs. In the context of computer-aided drug design, being able to calculate accurate, precise and reproducible binding free energies in silico is essential in terms of reducing the amount of trial-and-error synthetic effort required to develop a candidate drug. More potent and selective compounds will bind strongly to the desired target, and show weak binding to related proteins. Recent commercial software products have pushed the use of binding free energy calculations into mainstream development pipelines within the pharmaceutical industry. Even with pre-screening of suitable target systems, however, the required predictive accuracy of 1 kcal mol-1 is only attained in around half of cases. Determining whether sufficient accuracy has been achieved for a particular system is currently not possible a priori and requires expensive and time-consuming experimental validation. In this project the accuracy of these free energy calculations in the context of the pharmaceutical industry will be explored. We will develop a large dataset of test systems based on published data and determine the sensitivity of the calculated free energies to the choice of simulation software, parameters, free energy calculation method and system setup. Based on this sensitivity analysis, the project objectives are twofold: 1. To identify the primary causes of inaccuracy in protein-ligand binding free energy calculations. 2. To improve free energy calculation methodology to address these sensitivities.

蛋白质-配体结合自由能是用于发现和优化新药的关键性质。在计算机辅助药物设计的背景下，能够在计算机上计算准确，精确和可重复的结合自由能对于减少开发候选药物所需的试错合成工作量至关重要。更有效和选择性的化合物将与所需靶标强烈结合，并显示与相关蛋白质的弱结合。最近的商业软件产品已经将结合自由能计算的使用推向了制药行业的主流开发管道。然而，即使预先筛选合适的目标系统，所需的预测精度为1 kcal mol-1，只有在大约一半的情况下才能达到。确定特定系统是否已经达到足够的精度目前是不可能的先验，需要昂贵和耗时的实验验证。在这个项目中，这些自由能计算的准确性，在制药工业的背景下，将进行探讨。我们将根据已公布的数据开发一个大型的测试系统数据集，并确定计算的自由能对模拟软件、参数、自由能计算方法和系统设置的选择的敏感性。根据这一敏感性分析，项目目标有两个：1。确定蛋白质-配体结合自由能计算不准确的主要原因。2.改进自由能计算方法，以解决这些敏感性问题。