Drug Binding Free Energies with Implicit Solvent Methods

使用隐式溶剂方法的药物结合自由能

• 批准号: 7061270
• 负责人: Michael R Shirts
• 金额: $ 4.6万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7061270
• 关键词: chemical binding; chemical models; computer simulation; drug design /synthesis /production; ligands; method development; model design /development; molecular energy level; postdoctoral investigator; proteins; solvents; statistics /biometry

DESCRIPTION (provided by applicant): 1) To take standard implicit solvent models, combined with atomistic biomolecular models and modern sampling techniques, and attempt to directly evaluate the absolute free energy of ligand binding in a range of protein-ligand systems. 2) To develop statistical methods to identify of which, if any, of various sampling techniques are able to truly able to yield precise free energies of binding complexes for a range of relevant systems. 3) To use these results to identify ways in which the implicit solvent and atomistic biomolecular models can be improved to better fit the binding energies and structures for a wide variety of ligand protein complexes. This research has important consequences for rational drug design, and consequently all of medicine. If the predictive ability of biomolecular simulations can be significantly improved, and the efficiency of these methods increased, it will result in significantly lowered total costs of drug development.

描述（由申请人提供）：1）采用标准的隐式溶剂模型，结合原子生物分子模型和现代抽样技术，并尝试直接评估在一系列蛋白质配体系统中配体结合的绝对自由能。 2）开发统计方法，以确定各种采样技术的（如果有）能够真正能够为一系列相关系统产生结合复合物的精确自由能。 3）使用这些结果来确定可以改善隐式溶剂和原子生物分子模型的方法，以更好地适合各种配体蛋白质复合物的结合能和结构。这项研究对理性药物设计以及所有医学都有重要的影响。如果可以显着提高生物分子模拟的预测能力，并且这些方法的效率提高，则将大大降低药物开发的总成本。