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

利用溶剂化结构和热力学进行前瞻性药物发现和合理设计

基本信息

  • 批准号:
    9278586
  • 负责人:
  • 金额:
    $ 12.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-04-10 至 2021-02-28
  • 项目状态:
    已结题

项目摘要

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.
在药物结合时,水从蛋白质表面的位移具有重要的作用

项目成果

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Thomas Philip Kurtzman其他文献

Thomas Philip Kurtzman的其他文献

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{{ truncateString('Thomas Philip Kurtzman', 18)}}的其他基金

Solvation directed drug design: from molecular physics to lead optimization
溶剂化导向药物设计:从分子物理学到先导化合物优化
  • 批准号:
    10330792
  • 财政年份:
    2022
  • 资助金额:
    $ 12.38万
  • 项目类别:
Solvation directed drug design: from molecular physics to lead optimization
溶剂化导向药物设计:从分子物理学到先导化合物优化
  • 批准号:
    10664834
  • 财政年份:
    2022
  • 资助金额:
    $ 12.38万
  • 项目类别:
Solvation Directed Design of Flavonoid Derivatives for Caspase Inhibition
用于抑制 Caspase 的类黄酮衍生物的溶剂化定向设计
  • 批准号:
    8214271
  • 财政年份:
    2012
  • 资助金额:
    $ 12.38万
  • 项目类别:
Solvation Directed Design of Flavonoid Derivatives for Caspase Inhibition
用于抑制 Caspase 的类黄酮衍生物的溶剂化定向设计
  • 批准号:
    8458118
  • 财政年份:
    2012
  • 资助金额:
    $ 12.38万
  • 项目类别:
Exploiting Solvation Structure and Thermodynamics for Prospective Drug Discovery and Rational Design
利用溶剂化结构和热力学进行前瞻性药物发现和合理设计
  • 批准号:
    9461105
  • 财政年份:
    2012
  • 资助金额:
    $ 12.38万
  • 项目类别:
Solvation Directed Design of Flavonoid Derivatives for Caspase Inhibition
用于抑制 Caspase 的类黄酮衍生物的溶剂化定向设计
  • 批准号:
    8606468
  • 财政年份:
    2012
  • 资助金额:
    $ 12.38万
  • 项目类别:

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