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）：本R21探索性提案在合理开发可能有效缩短结核病治疗持续时间和/或改善耐多药结核病治疗的药物中使用了综合靶向方法。在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。一个这样的靶标是苹果酸合酶（MS）。已经表明MS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。最近在MS蛋白质的结构解析和MS功能测定的可用性方面的成功开辟了一条将计算机辅助药物设计方法与药物化学努力相结合以发现NRP TB的新治疗剂的途径。我们假设，这将是可能的识别和设计MS抑制剂使用计算机辅助药物设计和药物化学的组合。将在全细胞水平筛选在低微摩尔范围内显示抗MS活性的那些化合物，以确定其杀死复制型和NRP M的能力。在基于韦恩低氧模型的微孔板测定中，以及在哺乳动物细胞毒性方面的选择性，测定了结核病。这种迭代过程预计将产生几种低微摩尔，铅或药物样MS抑制剂。这些铅将是进一步开发的候选药物，包括更广泛的药物化学工作和后续项目中NRP动物模型的评价。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，并通过从头/合理的药物设计、虚拟聚焦组合库和市售化合物数据库的计算机筛选来识别新的抑制剂;合成最佳候选物;（2）测定候选药物对MS功能活性的抑制。(3)鉴定对活跃生长和/或非复制型持久性（NRP）结核分枝杆菌显示出显著选择活性的化合物。根据活性、细胞毒性和产生的选择性指数进行优先排序。公共卫生相关性：该提案旨在寻找新的苹果酸合酶抑制剂，这是非复制型持续性结核病的潜在新靶点。该项目首次汇集了一个与NRP相关的目标，苹果酸合酶，具有优化发现有用先导化合物的机会的化合物库，计算机辅助药物设计方法和药物化学。