Small molecule inhibitors pantothenate synthesis against M. tuberculosis

针对结核分枝杆菌的小分子泛酸合成抑制剂

• 批准号: 7243999
• 负责人: Pavel A Petukhov
• 金额: $ 18.81万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7243999
• 关键词: Animal Model; Animals; Biological Assay; Biology; Cells; Chemical Models; Chemicals; Chicago; Clinic; Communities; Computer Assisted; Consensus; Coughing; Data; Databases; Development; Docking; Drug Design; Drug Kinetics; Evaluation; Goals; Growth; HIV; Health; Illinois; Lead; Libraries; Ligands; Link; Mammalian Cell; Methods; Modeling; Molecular Weight; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Organic Synthesis; Organism; Oxygen; Pantoate-beta-alanine ligase; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Process; Proteins; Range; Rate; Records; Relapse; Research; Research Personnel; Resistance; Respiratory System; Screening procedure; Sneezing; Solid; Structure; Therapeutic; Therapeutic Agents; Toxic effect; Toxicology; Tuberculosis; Universities; Work; World Health Organization; analog; assay development; base; chemical synthesis; combinatorial; cytotoxicity; design; drug development; experience; improved; in vitro Model; indexing; inhibitor/antagonist; killings; molecular modeling; novel therapeutics; pantothenate; research and development; small molecule; success; therapy duration; tool; virtual

DESCRIPTION (provided by applicant): This R21 exploratory proposal uses an integrated target-oriented approach in the rational development of drugs that may effectively shorten the duration of therapy in tuberculosis and/or improve the treatment of multi-drug resistant TB. There exists a broad consensus in the TB research community that the key to shortening the duration of drug therapy without an increase in relapse rates lies in the specific targeting of proteins that are essential to the non-replicating persistence (NRP) of Mycobacterium tuberculosis. One such target is Pantothenate synthetase (PS). It has been shown that PS is crucial for persistent growth in mice and is over-expressed in in vitro models of NRP. Recent success in the structure elucidation of the PS protein and the availability of functional assays for PS opens a way to apply computer-aided drug design methods in concert with medicinal chemistry efforts to discover new therapeutic agents for NRP TB. We hypothesize that it would be possible to identify and design inhibitors for PS using a combination of computer-aided drug design and medicinal chemistry. Those compounds demonstrating activity at low micromolar range against PS will be screened at the whole cell level for the ability to kill replicating and NRP M. tuberculosis in a microplate assay based on the Wayne low oxygen model and for selectivity with respect to mammalian cell toxicity. This iterative process is expected to yield several low micromolar, lead- or drug- like inhibitors of PS. Such leads would be candidates for further development including more extensive medicinal chemistry efforts and the evaluation in animal models of NRP in subsequent projects. To achieve this goal, our specific aims are as follow: (1) Identify lead- or drug-like low molecular weight inhibitors of PS using a search for close analogs of the natural substrates of PS, docking of the databases of commercially available chemical compounds, de novo/rational drug design, virtual focused combinatorial libraries approaches; to synthesize the best lead candidates and analogs of the lead compounds if they are not commercially available; (2) Assay candidate drugs for their inhibition of PS functional activity. (3) Identify compounds demonstrating significant selective activity against actively growing and/or non-replicating, persistent (NRP) Mycobacterium tuberculosis. Prioritize on the basis of activity, cytotoxicity and resultant selectivity indices.

描述（由申请人提供）：该R21探索性提案在合理发展药物的合理发展中使用了综合目标方法，这些方法可能有效地缩短了结核病治疗的持续时间和/或改善耐多药TB的治疗。结核病研究界存在广泛的共识，即缩短药物治疗持续时间而不会增加复发率的关键在于蛋白质的特定靶向蛋白质对结核分枝杆菌的非复制持久性（NRP）至关重要。这样的靶标是泛素合成酶（PS）。已经表明，PS对于小鼠的持续生长至关重要，并且在NRP的体外模型中过表达。 PS蛋白的结构阐明的最新成功和PS的功能分析的可用性开辟了一种与药物化学努力一起应用计算机辅助药物设计方法的方法，以发现新的NRP TB治疗剂。我们假设可以使用计算机辅助药物设计和药物化学的组合来识别和设计PS的抑制剂。这些化合物将在整个细胞水平上筛选在低微摩尔范围内的活性，以杀死基于韦恩低氧模型的微孔板测定中的复制和NRP M.结核病。预计该迭代过程将产生PS的几种低微摩尔，铅或药物抑制剂。这样的潜在客户将是进一步发展的候选人，包括更广泛的药物化学工作以及随后项目中NRP动物模型的评估。为了实现这一目标，我们的具体目的如下：（1）使用搜索PS的自然基板的近距离模拟，识别PS的铅或药物样的低分子量抑制剂，对接市售化学化合物的数据库，DE NOVO/RECATICAL DEMATICAL DEMATICAL DEMATICS DEMATION DEMATION DEMATIAL，VILTUAL COSIFTUAL POSING POSISTIAL COMPOSINE COMPATISATION COMPIANIAL图书馆接近；合成铅化合物的最佳铅候选物和类似物，如果它们不可商购； （2）测定候选药物抑制PS功能活性。 （3）确定表现出显着选择性活性的化合物，以实现积极生长和/或非重复，持久性（NRP）结核分枝杆菌。根据活动，细胞毒性和结果选择性指数确定优先级。