Exploiting Solvation Structure and Thermodynamics for Prospective Drug Discovery and Rational Design

药物结合后蛋白质表面的水置换具有显着的影响，如果 不占主导地位，对识别自由能的贡献，因此起着重要作用 确定药物效力和特异性。尽管水在介导药物中很重要 蛋白质相互作用，常用的基于结构的模型并没有明确地将水视为 分子。相反，他们通过将配体-蛋白质接触分类为间接水合效应 疏水性或亲水性或将水建模为连续体。这些都不是 方法解释了水氢键的有限尺寸和定向性质， 其物理学对于描述密闭的不同环境的水合作用至关重要 蛋白质结合位点。在药物设计应用中采用简化的水处理 由于水化现象的复杂性和缺乏 基于分子的结构和热力学分析框架。近年来， PI 在开发两种利用非均匀流体的方法方面发挥了重要作用 溶剂化理论（IST）绘制水的溶剂化结构和热力学性质 蛋白质结合位点的分子细节：1) 水合位点分析 (HSA) 方法，该方法 构成了薛定谔有限责任公司的 WaterMap 的基础，并且 2) 相应的高分辨率网格 - 基于实现的 GIST，现已在免费分发的 AmberTools 中提供。这些中的每一个 分析工具绘制出 24 种独立的结构和热力学测量结果。 在这个提案中，我们将把溶剂化结构和热力学图合并到虚拟中 筛选和先导化合物优化方法，以提高我们的识别和设计能力 以高亲和力和特异性与家族目标成员结合的化合物 蛋白质。我们建议优化这些方法并将其应用于两个重要的药物靶点： 多巴胺受体 D3（药物成瘾治疗靶点）和 μ-OR 阿片类药物 受体，缓解疼痛的重要靶点。我们选择这些受体是因为 专门针对他们的挑战。脱靶结合通常会导致无法 发现可行的药物（D3）或具有显着不良副作用的药物（μ-OR）。 目前的方法在寻找这些目标的特定结合剂方面是无效的。因此 它们仍然是学术界和工业界都非常感兴趣的药物靶标 应用此处提出的新发现方法的自然选择。

The displacement of water from a protein surface upon the binding of a drug has a significant, if not dominant, contribution to the free energy of recognition, and hence plays a significant role in determining drug potency and specificity. Despite the importance of water in mediating drug- protein interactions, commonly used structure-based models do not explicitly treat water as a molecule. Instead, they indirectly hydration effects by categorizing ligand-protein contacts as either hydrophobic or hydrophilic or by modeling water as a continuum. Neither of these approaches accounts for the finite size and directed nature of water's hydrogen bonds, the physics of which is essential for describing the hydration of the diverse environment of confined protein binding sites. The adoption of simplified treatments of water in drug design applications has been made necessary by the complexity of hydration phenomena and the lack of a molecular-based framework for its structural and thermodynamic analysis. In recent years, the PI has been instrumental in developing two methodologies that utilize inhomogeneous fluid solvation theory (IST) to map out solvation structural and thermodynamic properties of water in molecular detail in protein binding sites: 1) A hydration site analysis (HSA) approach, which forms the basis for Schrodinger LLC's WaterMap and 2) A corresponding high-resolution grid- based implementation, GIST, now available in the freely distributed AmberTools. Each of these analysis tools maps out 24 independent measures of structure and thermodynamics. In this proposal we will incorporate solvation structure and thermodynamic maps into virtual screening and lead optimization methodologies to improve our ability to identify and design compounds that bind with high affinity and specificity to a targeted member of a family of proteins. We propose to optimize and apply these methods to two important drug targets: the dopamine receptor D3, a target for the treatment of drug addiction, and the μ-OR opioid receptor, an important target for pain alleviation. We have chosen these receptors because of the challenges of targeting them specifically. Off-target binding often results in either the inability to discover viable drugs (D3) or drugs which have significant undesirable side effects (μ -OR). Current methodologies have been ineffective in finding specific binders for these targets. Hence they remain drug targets of significant interest in both academic and industrial settings and the natural choice for the application of the new discovery methodologies proposed here.