权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Toward Rapid Rigorous Calculations of Binding Affinities

快速、严格地计算结合亲和力

基本信息

批准号：
6884539
负责人：
Frederick Martin Ytreberg
金额：
$ 4.99万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2006-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6884539
关键词：
aminoacid analog chemical binding coagulation factor X computational biology computer program /software computer simulation drug design /synthesis /production drug screening /evaluation method development phosphatase inhibitor phosphoprotein phosphatase postdoctoral investigator protease inhibitor

项目摘要

DESCRIPTION (provided by applicant): The objective of this research proposal is to further the development of rapid, rigorous calculations of binding affinities. The long-term goal is to provide techniques suitable for virtual screening of compounds for drug design. Existing rigorous methods for binding affinity calculations require long simulation and thus are not feasible for virtual screening. The proposed methods will calculate equilibrium binding affinities from non-equilibrium computer simulations for a range of molecular and protein systems. The aims are: (i) Develop practical guidelines for optimal use of standard non-equilibrium methods, along with a careful comparison between non-equilibrium and equilibrium methods; (ii) Extend non-equilibrium extrapolation techniques to protein-ligand systems, building on work by Zuckerman, Woolf and the applicant. These approaches overcome poor convergence properties of standard non-equilibrium calculations; {iii) Extend the single-simulation path sampling method to include molecular, then protein-ligand, systems within the TINKER software package. Developed by the applicant and Zuckerman, the method employs path-sampling to efficiently compute non-equilibrium-based affinity estimates.

描述（由申请人提供）：本研究提案的目的是进一步发展结合亲和力的快速、严格计算。长期目标是提供适合于药物设计的化合物的虚拟筛选的技术。现有的结合亲和力计算的严格方法需要长时间的模拟，因此不适用于虚拟筛选。所提出的方法将从一系列分子和蛋白质系统的非平衡计算机模拟计算平衡结合亲和力。其目标是：（i）为最佳使用标准非平衡方法制定实用准则，沿着对非平衡方法和平衡方法进行仔细比较;（ii）在Zuckerman、Woolf和申请人工作的基础上，将非平衡外推技术推广到蛋白质-配体系统。这些方法克服了标准非平衡计算的收敛性能差;（iii）扩展单模拟路径采样方法，包括分子，然后蛋白质配体，系统内的TINKER软件包。该方法由申请人和Zuckerman开发，采用路径采样来有效地计算基于非平衡的亲和力估计。