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

基本信息

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
项目类别：
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

项目摘要

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。这样的目标是苹果酸合酶（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。 MS蛋白质的结构阐明的最新成功和MS功能测定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NRP TB的新治疗剂。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MS的抑制剂。这些化合物表明，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。这种迭代过程有望产生MS的几种低微摩尔，铅或药物样抑制剂。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MS自然基质的紧密类似物，并使用DE NOVO/Rational Drugs Design鉴定新抑制剂，以识别MS的铅或药物样的低分子量抑制剂，并在对虚拟聚焦组合图书馆的硅筛选中鉴定新的抑制剂。综合最好的候选人；（2）测定候选药物抑制MS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。公共卫生相关性：该提案旨在找到新的苹果酸合酶抑制剂，这是非复制持续性结核病的潜在新目标。该项目首次汇集了与NRP相关的目标合酶，具有特性的化合物库，可优化找到有用的铅化合物，计算机辅助药物设计方法和药物化学的机会。