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首页> 外文学位 >The roles of structural variability and amphiphilicity of TMC278/rilpivirine in mechanisms of HIV drug resistance avoidance and enhanced oral bioavailability .
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The roles of structural variability and amphiphilicity of TMC278/rilpivirine in mechanisms of HIV drug resistance avoidance and enhanced oral bioavailability .

机译：TMC278 / rilpivirine的结构变异性和两亲性在避免HIV耐药性和增强口服生物利用度中的作用。

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摘要

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are small hydrophobic drug molecules that bind to a hydrophobic pocket of the HIV-1 reverse transcriptase (RT). A number of molecules from diarylpyrimidine (DAPY) class of NNRTIs have exceptional inhibitory properties against a broad range of known drug-resistant viral strains of HIV-1 and good oral bioavailability in humans. Biophysical, structural, and computational methods were applied to study DAPY NNRTIs with differing RT inhibitory and bioavailability properties with a goal to define the mechanisms by which the dual success of the selected DAPY NNRTIs is achieved.;Exceptional bioavailability properties of selected DAPY NNRTIs were hypothesized to stem from their ability to form self-formulated spherical drug aggregates, ∼60 nm in diameter, that are trafficked from the gastrointestinal tract into systemic circulation through a lymphatic uptake pathway. Using dynamic light scattering (DLS) and electron microscopy (EM), formation of drug aggregates was demonstrated. Drug aggregation was determined to be surfactant independent. Based on this observation, it was hypothesized that the drug molecules were able to achieve surface-active properties. Using X-ray crystallography and all atom MD simulations of the drug aggregate/water interface it was determined that amphiphilic properties of the selected DAPY NNRTI molecules depend on the availability of the protonation site at the pyrimidine ring and structural variability of the drug molecules at the linker moieties.;Ability of the late phase DAPY NNRTI drug molecules to inhibit the broad range of drug-resistant HIV-1 mutants has been previously linked to the ability of the molecules to sample multiple binding modes within the binding pocket of HIV-1 RT (Das et al., 2004). Using computational methods, conformational sampling by TMC278 (a DAPY NNRTI in multiple Phase III trials) in the pocket of the wild-type and the mutant NNRTIbinding pocket (NNIBP) was evaluated. Results of this work support the concept that structural variability is important in overcoming drug resistance mechanisms.;We propose that the implementation of drug aggregation testing and the evaluation of torsional flexibility of highly hydrophobic compounds in the context of the lead identification strategies will allow for better selection of potent and orally bioavailable hydrophobic drug candidates.
机译：非核苷逆转录酶抑制剂（NNRTIs）是小的疏水药物分子，与HIV-1逆转录酶（RT）的疏水口袋结合。许多来自二芳基嘧啶（DAPY）类NNRTI的分子对多种已知的HIV-1耐药药物毒株均具有优异的抑制特性，并在人类中具有良好的口服生物利用度。采用生物物理，结构和计算方法研究具有不同RT抑制和生物利用度特性的DAPY NNRTIs，以期确定实现所选DAPY NNRTIs双重成功的机制。由于它们形成直径约为60 nm的自配制球形药物聚集体的能力，这些聚集体从胃肠道通过淋巴吸收途径进入系统循环。使用动态光散射（DLS）和电子显微镜（EM），证明了药物聚集体的形成。确定药物聚集是与表面活性剂无关的。基于该观察，假设药物分子能够实现表面活性。使用X射线晶体学和药物聚集体/水界面的所有原子MD模拟，确定所选DAPY NNRTI分子的两亲性质取决于嘧啶环上质子化位点的可用性以及药物分子在嘧啶环上的结构变异性接头部分。晚期DAPY NNRTI药物分子抑制广泛耐药性HIV-1突变体的能力先前已与该分子在HIV-1 RT结合口袋内采样多种结合模式的能力相关联（Das等，2004）。使用计算方法，评估了TMC278（在多个III期试验中为DAPY NNRTI）在野生型和突变型NNRTIbinding袋（NNIBP）中的构象采样。这项工作的结果支持以下概念：结构变异性对克服耐药机制很重要。；我们建议在铅鉴定策略的背景下实施药物聚集测试和评估高度疏水性化合物的扭转挠性，将能够提供更好的解决方案选择有效的和口服可生物利用的疏水性药物候选物。

著录项

  • 作者

    Frenkel, Yulia.;

  • 作者单位

    Rutgers The State University of New Jersey - New Brunswick.;

  • 授予单位 Rutgers The State University of New Jersey - New Brunswick.;
  • 学科 Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 163 p.
  • 总页数 163
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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