Small Molecule Inhibitors of Malate Synthase against M. Tuberculosis

抗结核分枝杆菌的苹果酸合酶小分子抑制剂

• 批准号: 7897873
• 负责人: Pavel A Petukhov
• 金额: $ 19.63万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897873
• 关键词: Animal Model; Attenuated; Biological Assay; Cells; Chemicals; Chicago; Clinic; Communities; Computer Assisted; Computer Simulation; Consensus; Data; Databases; Development; Drug Design; Drug Kinetics; Enzymes; Evaluation; Generations; Glyoxylates; Goals; Growth; HIV; Health; Illinois; Immunocompetent; Lead; Libraries; Ligands; Link; Malate Synthase; Mammalian Cell; Methods; Modeling; Molecular Models; Molecular Weight; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Organic Synthesis; Oxygen; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Process; Property; Proteins; Records; Relapse; Research; Research Personnel; Screening procedure; Shunt Device; Solid; Structure; Therapeutic; Therapeutic Agents; Time; Toxic effect; Toxicology; Tuberculosis; Universities; Virulence; Work; World Health Organization; analog; animal efficacy; assay development; base; chemical synthesis; combinatorial; cytotoxicity; design; drug candidate; drug development; experience; glyoxylate; improved; in vitro Model; indexing; inhibitor/antagonist; killings; molecular modeling; novel therapeutics; public health relevance; research and development; small molecule; success; therapy duration; tuberculosis drugs; 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 malate synthase (MS). It has been shown that MS is crucial for persistent growth in mice and is over-expressed in vitro models of NRP. Recent success in the structure elucidation of the MS protein and the availability of functional assays for MS 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 MS using a combination of computer-aided drug design and medicinal chemistry. Those compounds demonstrating activity at low micromolar range against MS 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 MS. 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 MS using a search for close analogs of the natural substrates of MS and identification of new inhibitors using de novo/rational drug design, in silico screening of virtual focused combinatorial libraries and the databases of commercially available chemical compounds; to synthesize the best candidates; (2) Assay candidate drugs for their inhibition of MS 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. PUBLIC HEALTH RELEVANCE: This proposal is intended to find new malate synthase inhibitors, a potential new target for non- replicating persistent tuberculosis. This project brings together for the first time an NRP-associated target, malate synthase, libraries of compounds with properties that optimize the chances of finding useful lead compounds, computer-aided drug design approach, and medicinal chemistry.

描述（由申请人提供）：该R21探索性提案采用综合目标导向的方法合理开发药物，可有效缩短结核病治疗时间和/或改善耐多药结核病的治疗。结核病研究界达成广泛共识，即缩短药物治疗持续时间而不增加复发率的关键在于对结核分枝杆菌非复制持久性 (NRP) 至关重要的蛋白质进行特异性靶向。其中一种靶标是苹果酸合酶 (MS)。研究表明，MS 对于小鼠的持续生长至关重要，并且在 NRP 体外模型中过度表达。最近在 MS 蛋白的结构阐明和 MS 功能测定的可用性方面取得的成功，开辟了一条应用计算机辅助药物设计方法与药物化学工作相结合的方法，以发现 NRP 结核的新治疗剂。我们假设结合计算机辅助药物设计和药物化学，可以识别和设计多发性硬化症抑制剂。那些在低微摩尔范围内表现出抗 MS 活性的化合物将在全细胞水平上进行筛选，以确定其在基于韦恩低氧模型的微孔板测定中杀死复制型结核分枝杆菌和 NRP 结核分枝杆菌的能力，以及对哺乳动物细胞毒性的选择性。这一迭代过程预计会产生几种低微摩尔、先导或药物样的 MS 抑制剂。这些线索将成为进一步开发的候选者，包括更广泛的药物化学工作以及后续项目中 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）通过寻找MS天然底物的密切类似物来识别MS的先导或药物样低分子量抑制剂，并使用从头/理性识别新的抑制剂药物设计、虚拟聚焦组合库和市售化合物数据库的计算机筛选；综合最佳候选人； (2) 测定候选药物对MS功能活性的抑制作用。 (3) 鉴定对活跃生长和/或非复制持久性 (NRP) 结核分枝杆菌表现出显着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数确定优先顺序。公共健康相关性：该提案旨在寻找新的苹果酸合酶抑制剂，这是非复制性持续性结核病的潜在新靶点。该项目首次汇集了 NRP 相关靶标、苹果酸合酶、具有优化寻找有用先导化合物的机会的特性的化合物库、计算机辅助药物设计方法和药物化学。