Ligand-based Design of Anti-HIV Therapeutics Targeting gp41

基于配体的 gp41 抗 HIV 治疗药物设计

• 批准号: 8639971
• 负责人: William J Allen
• 金额: $ 5.33万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639971
• 关键词: Algorithmic Software; Area; Binding; C-Peptide; Chemicals; Combined Modality Therapy; Communities; Complex; Development; Disease; Docking; Drug Targeting; Drug resistance; FDA approved; Fellowship; Fingerprint; Free Energy; Goals; HIV; Health; Injection of therapeutic agent; Knowledge; Lead; Libraries; Life; Ligand Binding; Ligands; Literature; Mediating; Membrane Fusion; Methods; Mission; Modification; Molecular; Outcome; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Process; Property; Public Health; Quantitative Structure-Activity Relationship; Reporting; Research; Series; Side; Structure; System; Techniques; Therapeutic; Treatment Cost; Viral; Virus; Virus Diseases; Work; base; burden of illness; chemical property; cheminformatics; combat; design; disability; drug discovery; functional group; global health; glycoprotein 41; improved; inhibitor/antagonist; innovation; molecular dynamics; next generation; novel therapeutics; pharmacophore; prevent; programs; public health relevance; receptor; research study; resistance mutation; scaffold; screening; simulation; small molecule; therapeutic target; virtual

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) infection remains a significant public and global health threat. Our long-term goal is the development of small molecule fusion inhibitors to be used as anti-HIV therapeutics. The specific objective of this proposal is to generate new drug leads which bind tightly to a highly-conserved deep pocket formed by the gp41 N-heptad repeat trimer. Our central hypothesis is that known gp41 inhibitors (including small molecules and peptides) can act as reference molecules to facilitate and drive the discovery of new leads. The hypothesis is motivated in part by the Sponsor's Lab's development and application of a new receptor-based method (called per-residue footprint comparisons) which employed the known peptide inhibitor C34 to successfully identify small-molecule leads with gp41 activity. The present postdoctoral application emphasizes an orthogonal ligand-based approach which uses chemical information inherent to peptide inhibitors as well as reported small molecule inhibitors. Ligand properties including 2D fingerprint similarity, 3D pharmacophores, and volume overlap will be used to design new gp41 drug-lead candidates. The rationale for the proposed work is that the design of large ensembles of compounds with chemical properties tailored to a reference, or a combination of references, will enable discovery of new gp41 inhibitors as leads for development of anti-HIV therapeutics. The proposed research can be arranged as the following specific aims: 1) Construct new small-molecule gp41 inhibitors from scratch guided by cheminformatic and molecular properties of known small-molecule and peptide inhibitors, 2) Optimize functionality for select gp41 inhibitors (Holden et al., 2012) to maximize property overlap with available crystallographic peptide co-complexes, and 3) Establish quantitative-structure-activity-relationships with experiment for congeneric series of gp41 inhibitors reported in the literature (Zhou et al., 2010; Stewart et al., 2010; Jiang et al., 2011). Under the first aim, new small molecules will be constructed from building block libraries, guided by the chemical information inherent to known C-peptides and reported small molecule inhibitors. Under the second aim, known small molecule inhibitors will be improved through SAR modification of functional groups to more completely mimic key peptide side chain properties. Under the third aim, receptor-based docking will be employed to effectively identify low- energy ligand binding poses of known gp41 inhibitors, followed by molecular simulation to establish a quantitative correlation with experiment. This primarily ligand-based approach is innovative because it is designed to search a new area in chemical space and ultimately converge upon a distinct subset of potential fusion inhibitors targeting HIV gp41. The proposed research is significant because it is likely to aid in the development of new therapeutics for the treatment of HIV, ultimately contributing to the NIH's mission to "enhance health, lengthen life, and reduce the burdens of illness and disability".

描述（由申请人提供）：人类免疫缺陷病毒（HIV）感染仍然是一个重大的公共和全球健康威胁。我们的长期目标是开发小分子融合抑制剂作为抗HIV治疗剂。该提议的具体目标是产生新的药物先导物，其紧密结合由gp 41 N-七肽重复三聚体形成的高度保守的深口袋。我们的中心假设是，已知的gp 41抑制剂（包括小分子和肽）可以作为参考分子，以促进和推动新线索的发现。该假设的部分动机是申办方实验室开发和应用了一种新的基于受体的方法（称为每残基足迹比较），该方法采用已知的肽抑制剂C34成功鉴定了具有gp 41活性的小分子先导化合物。本博士后申请强调了一种基于正交配体的方法，该方法使用肽抑制剂以及报道的小分子抑制剂固有的化学信息。包括2D指纹相似性，3D药效团和体积重叠在内的配体特性将用于设计新的gp 41药物先导候选物。拟议工作的基本原理是，设计具有参考或参考组合的化学性质的化合物的大集合，将能够发现新的gp 41抑制剂作为开发抗HIV治疗剂的先导。所提出的研究可以安排为以下具体目标：1）通过已知小分子和肽抑制剂的化学信息学和分子性质指导，从头开始构建新的小分子gp 41抑制剂，2）优化选择gp 41抑制剂的功能（霍尔顿等人，2012）以最大化与可用的晶体学肽共复合物的性质重叠，和3）与文献中报道的gp 41抑制剂的同类系列的实验建立定量-结构-活性-关系（Zhou et al.，2010; Stewart等人， 2010年; Jiang等人，2011年）。在第一个目标下，新的小分子将从构建块库中构建，由已知C肽和报告的小分子抑制剂固有的化学信息指导。在第二个目标下，将通过官能团的SAR修饰来改进已知的小分子抑制剂，以更完全地模拟关键肽侧链性质。在第三个目标下，将采用基于受体的对接来有效地鉴定已知gp 41抑制剂的低能配体结合位姿，随后通过分子模拟来建立与实验的定量相关性。这种主要基于配体的方法是创新的，因为它旨在寻找化学空间中的一个新领域，并最终集中在靶向HIV gp 41的潜在融合抑制剂的不同子集上。这项拟议中的研究意义重大，因为它可能有助于开发治疗艾滋病毒的新疗法，最终有助于实现NIH的使命，即“增强健康，延长寿命，减轻疾病和残疾的负担”。