New Hydropathy-Based computer Tools for Drug Discovery

描述(由申请人提供)：这个项目的总体目标是开发一套新的集成软件应用程序，用于预测、精炼和操纵生物大分子结构，特别是关于候选药物的计算虚拟筛选。针对生物大分子靶标的一组配基的虚拟筛选需要配基结合位置的高度准确的模型，以及快速有效地估计结合亲和力。在许多重要的药物发现项目中，这两个要求都无法满足。因此，这项研究的两个主要目标是：1)提高假定的蛋白质-配体复合体自由能评分的准确性和可靠性；2)提高来自X射线、核磁共振或比较建模的低分辨率结构模型的质量，使它们成为虚拟筛选的目标。这项研究计划的核心技术是基于(以合理的速度和精度)输出(以合理的速度和精度)输出独特的经验自由能力场和编码重要结构信息的三维图形对象的HINT(流体相互作用)程序/范例。这项工作将创建一系列特定的软件工具：a)使用提示力场计分的集成对接系统；b)评估残基和配体官能团的电离状态以优化配体结合的自动化计算滴定程序；c)一系列方法来预测和/或优化水分子在水介导的氢键可能影响配体结合的环境中的位置；d)基于三维疏水图的新的从头配体设计方案；以及e)以水路径力场为目标函数的集成结晶学和核磁共振精化程序(S)。后一种工具可以扩展为同源建模方法的附件，以创建目标结构，并可能被证明对定义不可访问蛋白质的模型有用。已经有了具体的合作安排，以将这些工具应用于一系列当前的药物发现问题。

DESCRIPTION (provided by applicant): The overall aim of this project is to develop a novel integrated suite of software applications for predicting, refining and manipulating biomacromolecular structure, particularly with respect to computational virtual screening of drug candidates. Virtual screening of a panel of ligands against a biomacromolecule target requires a highly accurate model for the ligand binding site, as well as rapid and effective estimation of binding affinity. In many important drug discovery projects both of these requirements cannot be met. The two main goals of the proposed research are thus to: 1) improve the accuracy and relability of free energy scoring of putative protein-ligand complexes, and 2) enhance the quality of low-resolution structural models from x-ray, nmr or comparative modeling to make them useful as targets for virtual screening. The core technology for this research plan is based on the HINT (Hydropathic INTeractions) program/paradigm that exports (with reasonable speed and accuracy) both a unique empirical free energy forcefield and threedimensional graphics objects that encode significant structural information. A number of specific software tools will be created by this effort: a) an integrated docking system using HINT forcefield scoring; b) an automated computational titration program that evaluates the ionization state of residues and ligand functional groups to optimize ligand binding; c) a range of methods to predict and/or optimize water molecule locations in environments where water-mediated hydrogen bonding could impact ligand binding; d) a new de novo ligand design protocol based on three-dimensional hydropathy maps; and e) integrated crystallographic and NMR refinement program(s) using the hydropathic forcefield as a target function. This latter tool may be extended as an adjunct to homology modeling approaches to creating target structures, and may prove useful for defining models of inaccessible proteins. Specific collaborative arrangements are in place to apply these tools to a range of current drug discovery problems.