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

当药物结合时，蛋白质表面的水置换具有显著的，如果 不占主导地位，对认识的自由能有贡献，因此起着重要作用 在确定药物效力和特异性方面。尽管水在调停毒品方面很重要- 蛋白质相互作用，通常使用的基于结构的模型并不明确地将水视为 分子。相反，它们通过将配体-蛋白质接触归类为 可以是疏水的，也可以是亲水的，或者通过将水模拟为一个连续体来实现。这两个都不是 方法解释了水的氢键的有限大小和定向性质， 它的物理特性对于描述密闭环境的水化作用是必不可少的。 蛋白质结合部位。在药物设计应用中采用简化的水处理方法 由于水合现象的复杂性和缺乏 为其结构和热力学分析提供了基于分子的框架。近几年来， PI在开发利用非均质流体的两种方法方面发挥了重要作用 用溶剂化理论(IST)研究水的溶剂化结构和热力学性质 蛋白质结合部位的分子细节：1)水合部位分析(HSA)方法，它 构成了薛定谔有限责任公司水图的基础和2)相应的高分辨率网格- 基于实现的GIST，现在可在免费分发的AmberTool中使用。这其中的每一个 分析工具绘制了24个独立的结构和热力学测量数据。 在这个提议中，我们将把溶剂化结构和热力学映射结合到虚拟 筛选和领导优化方法，以提高我们识别和设计的能力 以高亲和力和特异性结合到目标成员家族中的化合物 蛋白质。我们建议将这些方法优化并应用于两个重要的药物靶点： 治疗药物成瘾的靶标多巴胺受体D3和μ-OR阿片类药物 受体，是缓解疼痛的重要靶点。我们之所以选择这些受体，是因为 专门针对他们的挑战。脱离目标的绑定通常会导致无法 发现可行的药物(D3)或有显著不良副作用的药物(μ-OR)。 目前的方法在为这些目标寻找具体的结合剂方面效率低下。因此 它们仍然是学术界和工业界非常感兴趣的药物靶标， 这里提出的新的发现方法的应用是自然的选择。

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.