New Hydropathy-Based computer Tools for Drug Discovery

描述（由申请人提供）：本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，特别是在候选药物的计算虚拟筛选方面。针对生物大分子靶标的一组配体的虚拟筛选需要配体结合位点的高度精确的模型，以及结合亲和力的快速有效的估计。在许多重要的药物发现项目中，这两个要求都不能满足。因此，拟议研究的两个主要目标是：1）提高推定蛋白质-配体复合物自由能评分的准确性和可靠性，以及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有用目标。这项研究计划的核心技术是基于HINT（Hydropathic Interactions）程序/范式，该程序/范式（以合理的速度和准确性）导出了一个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。通过这一努力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）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计算滴定程序; c）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的一系列方法; d）基于三维亲水图的新的从头配体设计方案;和后一种工具可以作为同源建模方法的辅助工具来扩展以创建目标结构，并且可以证明对于定义难以接近的蛋白质的模型是有用的。具体的合作安排已经到位，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.