Design of multi-target D-Ala-D-Ala ligase ligands

多靶点D-Ala-D-Ala连接酶配体的设计

基本信息

批准号：
8098979
负责人：
Judith Varady Hobrath
金额：
$ 32.03万
依托单位：
SOUTHERN RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8098979
关键词：
Adverse effects Affinity Agonist Alanine Alanine Racemase Anabolism Anti-Bacterial Agents Antibiotics Antimycobacterial Agents Binding Binding Sites Biochemical Process Biological Assay Cell Wall Cells Cessation of life Computer Simulation Crude Extracts Cycloserine Cytolysis D-Alanine-D-alanine ligase Data Development Dipeptides Divalent Cations Drug Design Effectiveness Enterococcus Enzymes Epidemic Escherichia coli Essential Genes Extreme drug resistant tuberculosis Funding Genus Mycobacterium Growth Health Human Lateral Lead Ligand Binding Ligands Multi-Drug Resistance Mutagenesis Mycobacterium smegmatis Mycobacterium tuberculosis N-Methylaspartate Nebraska Osmotic Pressure Outcome Peptides Peptidoglycan Pharmaceutical Preparations Phosphotransferases Physiological Processes Population Process Proteins Protocols documentation Reaction Reporting Resistance Resolution Salmonella typhimurium Screening procedure Site Staphylococcus aureus Structure Texas Therapeutic Agents Toxic effect Universities Validation Vertebral column analog antimicrobial drug assay development bactericide base crosslink design drug development enantiomer enzyme mechanism inorganic phosphate microorganism mycobacterial neurotransmission novel novel therapeutics pathogen receptor resistant strain scaffold stem tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis is a major epidemic today, causing 8 million new cases and 3 million deaths yearly world-wide. New anti-tubercular drugs that act through novel mechanisms are urgently needed for more efficacious treatments in combination with existing drugs and for treating multi-drug resistant strains that emerged in recent years. The bacterial cell wall contains peptidoglycan that provides resistance from external osmotic pressure. Targeting steps of peptidoglycan biosynthesis is an attractive mechanism for new antibacterial agents. An essential step is the synthesis of D-Alanyl-D-Alanine dipeptide (D-Ala-D-Ala) that is required for the formation of peptidoglycan and for cross-linking peptidoglycan strands. The enzyme catalyzing this process is D-Alanyl-D-Alanine ligase (DDl). DDl is an excellent target for new antibiotics since synthesis of D-Ala-D-Ala is an essential process for bacterial growth and furthermore there is no human equivalent to DDl. We have applied an in silico structure based approach to identify and assay DDl ATP and substrate site binding ligands using sets of compounds that have shown activity against M. tuberculosis TB H37Rv in HTS screening and kinase binding ligands that show structural similarities to DDl. We propose to refine and validate DDl binding prediction protocols in the first half of the proposed effort and utilize these to identify and assay compounds based on known scaffolds of valid anti-tubercular targets for activity against DDl. PUBLIC HEALTH RELEVANCE: New anti-tubercular drugs that act through novel mechanisms are urgently needed for more efficacious treatments of tuberculosis and for treating multi-drug resistant strains that recently emerged. In this proposal we have apply an in silico structure based approach to identify and assay novel potent DDl binders and multi- TB target ligands.

描述（由申请人提供）：结核分枝杆菌是当今的一种主要流行病，每年在全世界造成 800 万新病例和 300 万人死亡。迫切需要通过新机制发挥作用的新型抗结核药物，以便与现有药物联合使用，以实现更有效的治疗，并治疗近年来出现的多重耐药菌株。细菌细胞壁含有肽聚糖，可抵抗外部渗透压。肽聚糖生物合成的靶向步骤是新型抗菌剂的一个有吸引力的机制。一个重要步骤是合成 D-丙氨酰-D-丙氨酸二肽 (D-Ala-D-Ala)，这是形成肽聚糖和交联肽聚糖链所必需的。催化该过程的酶是D-丙氨酰-D-丙氨酸连接酶(DD1)。 DD1是新抗生素的极好靶标，因为D-Ala-D-Ala的合成是细菌生长的重要过程，而且人类中没有DD1的等同物。我们已经应用基于计算机结构的方法来鉴定和测定DD1 ATP和底物位点结合配体，使用在HTS筛选中表现出抗结核分枝杆菌TB H37Rv活性的化合物组和表现出与DD1结构相似性的激酶结合配体。我们建议在所提出的努力的前半部分中完善和验证DD1结合预测方案，并利用这些方案来基于有效抗结核靶标的已知支架来鉴定和测定化合物的针对DD1的活性。公共卫生相关性：迫切需要通过新机制发挥作用的新型抗结核药物，以更有效地治疗结核病和治疗最近出现的多重耐药菌株。在该提议中，我们应用基于计算机结构的方法来鉴定和测定新型有效的DD1结合剂和多TB靶配体。