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）：本R21探索性提案在合理开发药物时使用了一种综合的靶向方法，可以有效缩短结核病的治疗时间和/或改善对多重耐药结核病的治疗。在结核病研究界存在着广泛的共识，即缩短药物治疗时间而不增加复发率的关键在于特异性靶向对结核分枝杆菌的非复制持久性（NRP）至关重要的蛋白质。其中一个目标是泛酸合成酶（PS）。研究表明，PS对小鼠的持续生长至关重要，并在体外NRP模型中过度表达。最近在PS蛋白结构解析方面的成功和PS功能分析的可用性为将计算机辅助药物设计方法与药物化学工作相结合，发现新的治疗NRP结核病的药物开辟了一条道路。我们假设使用计算机辅助药物设计和药物化学相结合的方法来识别和设计PS抑制剂是可能的。这些化合物在低微摩尔范围内显示出对PS的活性，将在全细胞水平上进行筛选，以在基于Wayne低氧模型的微孔板试验中杀死复制和NRP结核分枝杆菌的能力，并对哺乳动物细胞毒性进行选择性筛选。这一迭代过程有望产生几种低微摩尔，铅或药物样的PS抑制剂。这些铅将成为进一步开发的候选物，包括更广泛的药物化学努力和后续项目中NRP动物模型的评估。为了实现这一目标，我们的具体目标如下：(1)通过搜索PS的天然底物的接近类似物，对接市售化合物数据库，重新设计/合理药物设计，虚拟聚焦组合文库方法，确定铅或药物样的低分子量PS抑制剂；合成最佳的先导化合物候选物和先导化合物的类似物，如果它们不是市售的；(2)测定候选药物对PS功能活性的抑制作用。(3)鉴定对活性生长和/或非复制持续性（NRP）结核分枝杆菌具有显著选择性活性的化合物。根据活性、细胞毒性和由此产生的选择性指标进行排序。