New Hydropathy-Based computer Tools for Drug Discovery

描述（由申请人提供）：该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体的虚拟筛选需要一个高度精确的配体结合位点模型，以及快速有效的结合亲和力估计。在许多重要的药物发现项目中，这两个要求无法同时满足。因此，提出的研究的两个主要目标是：1)提高假定的蛋白质配体复合物自由能评分的准确性和可靠性；2)提高x射线，核磁共振或比较建模的低分辨率结构模型的质量，使其成为虚拟筛选的靶标。该研究计划的核心技术是基于HINT （Hydropathic INTeractions）程序/范例，该程序/范例（以合理的速度和准确性）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。通过这项工作将创建一些特定的软件工具：A)使用HINT力场评分的集成对接系统；B)自动计算滴定程序，评估残基和配体官能团的电离状态，以优化配体结合；C)在水介导的氢键可能影响配体结合的环境中，预测和/或优化水分子位置的一系列方法；D)基于三维水情图的全新配体设计方案；e)使用亲水力场作为目标函数的集成晶体学和核磁共振细化程序。后一种工具可以扩展为同源建模方法的辅助工具，以创建目标结构，并且可能被证明对定义不可接近的蛋白质模型有用。具体的合作安排已经到位，以便将这些工具应用于当前的一系列药物发现问题。

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.