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首页> 外文学位 >Understanding molecular interactions: Applications of HINT-based tools in the structural modeling of novel anticancer and antiviral targets, and in protein-protein docking.
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Understanding molecular interactions: Applications of HINT-based tools in the structural modeling of novel anticancer and antiviral targets, and in protein-protein docking.

机译：了解分子相互作用：基于HINT的工具在新型抗癌和抗病毒靶标的结构建模中以及在蛋白质-蛋白质对接中的应用。

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摘要

Computationally driven drug design/discovery efforts generally rely on accurate assessment of the forces that guide the molecular recognition process. HINT (Hydropathic INTeraction) is a natural force field, derived from experimentally determined partition coefficients that quantifies all non-bonded interactions in the biological environment, including hydrogen bonding, electrostatic and hydrophobic interactions, and the energy of desolvation. The overall goal of this work is to apply the HINT-based atomic level description of molecular systems to biologically important proteins, to better understand their biochemistry - a key step in exploiting them for therapeutic purposes.;This dissertation discusses the results of three diverse projects: i) structural modeling of human sphingosine kinase 2 (SphK2, a novel anticancer target) and binding mode determination of an isoform selective thiazolidine-2,4-dione (TZD) analog; ii) structural modeling of human cytomegalorvirus (HCMV) alkaline nuclease (AN) UL98 (a novel antiviral target) and subsequent virtual screening of its active site; and iii) explicit treatment of interfacial waters during protein-protein docking process using HINT-based computational tools.;SphK2 is a key regulator of the sphingosine-rheostat, and its upregulation /overexpression has been associated with cancer development. We report structural modeling studies of a novel TZD-analog that selectively inhibits SphK2, in a HINT analysis that identifies the key structural features of ligand and protein binding site responsible for isoform selectivity.;The second aim was to build a three-dimensional structure of a novel HCMV target – AN UL98, to identify its catalytically important residues. HINT analysis of the interaction of 5' DNA end at its active site is reported. A parallel aim to perform in silico screening with a site-based pharmacophore model, identified several novel hits with potentially desirable chemical features for interaction with UL98 AN.;The majority of current protein-protein docking algorithms fail to account for water molecules involved in bridging interactions between partners, mediating and stabilizing their association. HINT is capable of reproducing the physical and chemical properties of such waters, while accounting for their energetic stabilizing contributions. We have designed a solvated protein-protein docking protocol that explicitly models the Relevant bridging waters, and demonstrate that more accurate results are obtained when water is not ignored.
机译：计算驱动的药物设计/发现工作通常依赖于对指导分子识别过程的作用力的准确评估。 HINT（Hydropathic INTeraction）是一种自然力场，它是由实验确定的分配系数得出的，该分配系数可量化生物环境中所有未键合的相互作用，包括氢键，静电和疏水相互作用以及去溶剂化的能量。这项工作的总体目标是将分子系统的基于HINT的原子水平描述应用于生物学重要的蛋白质，以更好地了解其生物化学，这是将其用于治疗目的的关键步骤。;本论文讨论了三个不同项目的结果：i）人鞘氨醇激酶2（SphK2，新型抗癌靶标）的结构建模和同工型选择性噻唑烷-2,4-二酮（TZD）类似物的结合模式测定； ii）人巨细胞病毒（HCMV）碱性核酸酶（AN）UL98（一种新型抗病毒靶标）的结构建模以及随后对其活性位点的虚拟筛选； iii）使用基于HINT的计算工具在蛋白质-蛋白质对接过程中对界面水进行显式处理。; SphK2是鞘氨醇变阻器的关键调节剂，其上调/过表达与癌症的发展有关。我们在HINT分析中报告了一种选择性抑制SphK2的新型TZD类似物的结构建模研究，该分析确定了负责同工型选择性的配体和蛋白质结合位点的关键结构特征;第二个目标是构建三维结构一种新型HCMV靶标– UL98，以鉴定其催化重要的残基。报道了5'DNA末端在其活性位点的相互作用的HINT分析。使用基于位点的药效团模型进行计算机筛选的并行目标是，鉴定出几种具有与UL98 AN相互作用可能具有所需化学特征的新型命中物;大多数当前的蛋白质-蛋白质对接算法无法解释涉及桥接的水分子伙伴之间的互动，调解和稳定他们的联系。提示能够再现这些水的物理和化学特性，同时考虑到它们的能量稳定作用。我们设计了一种溶剂化的蛋白质-蛋白质对接方案，可以对相关的桥接水进行显式建模，并证明在不忽略水的情况下可以获得更准确的结果。

著录项

  • 作者

    Parikh, Hardik I.;

  • 作者单位

    Virginia Commonwealth University.;

  • 授予单位 Virginia Commonwealth University.;
  • 学科 Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 207 p.
  • 总页数 207
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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