MOLECULAR MODELING STUDIES AND SAR OF ANTI-HIV AGENTS

迄今为止，还没有系统的构效关系研究 (SAR)使用现代理论方法研究抗艾滋病毒核苷， 公开. 然而，已经表明，在固态下， 类似物表现出中度到极端的S型呋喃糖构象 （伪旋转角P高达215度）。 根据这一线索，使用 构象分析的原则，人们可以合理化的活动或 其他核苷类似物的无活性（包括许多尚未研究的 X射线方法）就取代基对呋喃糖环的影响而言 构象 这样的分析表明，S型构象是 在所有活性核糖类似物中稳定（相对于N型），而 这种效应在大多数无活性化合物中不存在。 一个现行假设 基于NMR研究的相关性， 构象（P> 180 °）05'的+sc取向不稳定， 增加对AP方向的访问，这可能更有利于 活动 “笨拙效应”是N/S的主要决定因素 构象平衡，并且可以进行显著的相关性 3'取代的THY类似物的活性与 取代基的构象偏好（如通过MNDO确定的 对取代的乙醇的计算）。 初步结果还表明， 由分子力学（MM）确定的低能构象与 与观察到的抗HIV核苷的晶体结构很好，但要小心 需要参数化以准确确定相对 能量 从头算和半经验量子力学计算将 可用于开发MM参数，以准确地模拟笨拙， 核苷中的异头效应（通常在大多数现有力中缺乏 场），并确定构象能量学和电子 核苷的结构。 这里描述的初步结果将是 通过对活性和非活性化合物的综合研究（例如， BCH-189，其活性支持我们的构象假设）， 检查这些变量，如构象，空间体积，疏水性， 分子静电势和氢键。 所陈述的 工作假设将被测试，放大和/或修改，并强调 将致力于开发具有可测试预测价值的模型。 结果将普遍提供，以协助研究人员在 艾滋病抗病毒药物开发领域。

To date, no systematic studies of the structure-activity relationships (SAR) of anti-HIV nucleosides using modern theoretical methods have been published. However, it has been shown that in the solid state active analogs exhibit moderate to extreme S-type furanose conformations (pseudorotational angle P up to 215degrees). Following this lead, using principles of conformational analysis, one can rationalize the activity or inactivity of other nucleoside analogs (including many not yet studied by X-ray methods) in terms of the effects of substituents on the furanose ring conformation. Such an analysis shows that S-type conformations are stabilized (relative to N-type) in all the active ribose analogs, whereas this effect is absent in most inactive compounds. A working hypothesis based on correlations from NMR studies is that in extreme S-type conformations (P>180degrees) the +sc orientation of 05' is destabilized, increasing access to the ap orientation, which may be more favorable for activity. The "gauche effect" is a major determinant of the N/S conformational equilibrium, and a significant correlation can be made between activity of 3' substituted THY analogs and the gauche/trans conformational preference of the substituents (as determined by MNDO calculations on substituted ethanols). Preliminary results also indicate that low energy conformers determined by molecular mechanics (MM) correlate well with observed crystal structures for anti-HIV nucleosides, but careful parameterization is required for accurate determination of relative energies. Ab initio and semiempirical quantum mechanics calculations will be used to develop MM parameters to accurately model the gauche and anomeric effects in nucleosides (generally lacking in most current force fields) and to determine conformational energetics and electronic structures of nucleosides. The preliminary results described here will be extended by comprehensive studies of active and inactive compounds (e.g. BCH-189, the activity of which support our conformational hypothesis), examining such variables as conformation, steric bulk,, hydrophobicity, molecular electrostatic potentials and hydrogen bonding. The stated working hypothesis will be tested, amplified and/or modified, and emphasis will be placed on the development of models with testable predictive value. Results will be made generally available to assist researchers working in the area of AIDS antiviral drug development.