Solvent Modeling for HIV RT Drug Design

HIV RT 药物设计的溶剂建模

• 批准号: 7023777
• 负责人: DANIEL M HIMMEL
• 金额: $ 5.4万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-08 至 2007-03-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7023777
• 关键词: X ray crystallography; antiAIDS agent; binding sites; bioimaging /biomedical imaging; chemical models; drug design /synthesis /production; endoribonucleases; enzyme activity; human immunodeficiency virus 1; postdoctoral investigator; protein binding; protein structure; reverse transcriptase inhibitors; ribonuclease H; small molecule; solvents; structural biology

DESCRIPTION (provided by applicant): One of the key pharmacological targets in the fight against AIDS is HIV-1 reverse transcriptase (RT), which controls a number of essential steps in viral replication. In the current proposal, new structural biological approaches will be applied to develop RT inhibitors. One approach will be an adaptation of the "multiple solvent crystal structures" method, in which small organic molecules are soaked into RT crystals to probe for possible inhibitor binding sites. This strategy will be augmented by a second approach, in which existing crystallographic equations will be modified to account for X-ray scattering by semi-ordered solvent molecules. This ability to phase a portion of the solvent around a protein could to lead to sharper, more interpretable electron density images of protein structure and small molecules bound to the protein. Visualization of these small bound molecules can provide the rationale for designing the backbones for new, highly specific drug prototypes. This method will be applied to improve refinement for a new class of RT inhibitors (see preliminary results). The method may advance the field of macromolecular X-ray crystallography, opening up new opportunities for structure-based drug design to treat AIDS and a variety of other disorders.

描述（由申请人提供）：与艾滋病作斗争的关键药理目标之一是HIV-1逆转录酶（RT），它控制了病毒复制的许多基本步骤。在当前的建议中，将采用新的结构生物学方法来开发RT抑制剂。一种方法将是对“多个溶剂晶体结构”方法的适应，其中将小的有机分子浸入RT晶体中以探测可能的抑制剂结合位点。该策略将通过第二种方法来增强，其中将修改现有的晶体学方程，以通过半排序的溶剂分子来考虑X射线散射。这种能够在蛋白质周围溶剂的一部分的能力，可以导致蛋白质结构的更清晰，更容易解释的电子密度图像和与蛋白质结合的小分子。这些小结合分子的可视化可以为设计新的，高度特定的药物原型设计骨干提供理由。该方法将用于改善新的RT抑制剂的细化（请参阅初步结果）。该方法可能会推进大分子X射线晶体学领域，从而为基于结构的药物设计和其他各种疾病打开了新的机会。