Discovery of Thymidylate Kinase Inhibitors for Anti-Fungal Applications

发现用于抗真菌应用的胸苷酸激酶抑制剂

基本信息

批准号：
10453065
负责人：
GORDON S. RULE
金额：
$ 19.6万
依托单位：
CARNEGIE-MELLON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-18 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453065
关键词：
Affinity Antifungal Agents Antifungal Therapy Azoles Binding Biological Assay Biology Candida Candida albicans Candida auris Candidiasis Catheters Chemicals Clinical DNA Repair DNA biosynthesis DNA metabolism Dangerousness Data Development Diphosphates Diversity Library Docking Drug Evaluation Drug resistance Enzymatic Biochemistry Enzyme Stability Enzymes Evaluation Feedback Fluconazole Fluorescence Goals Growth Human Human Cell Line Immunocompromised Host Implant Infection Lead Libraries Ligands Location Machine Learning Measures Medical Methods Microbial Biofilms Minimum Inhibitory Concentration measurement Mycoses Nuclear Magnetic Resonance Nucleotides Oranges Pharmaceutical Preparations Phosphorylation Population Production Property Proteins Quantitative Structure-Activity Relationship Reproducibility Research Project Grants Signal Transduction Site Specificity Structure Structure-Activity Relationship Testing Thymidine Monophosphate Time Toxic effect X-Ray Crystallography Yeasts analog base candidate selection computational chemistry computerized tools drug discovery functional group high throughput screening inhibitor kinase inhibitor medical implant mortality novel pathogen pathogenic fungus protein protein interaction resistant strain screening small molecule inhibitor small molecule libraries thymidylate kinase virtual screening

项目摘要

Discovery of Thymidylate Kinase Inhibitors for Anti-Fungal Applications Abstract: Infections due to the fungal pathogen Candida albicans are devastating to the human population. C. albicans causes over 40,000 cases of invasive candidiasis/year in the US alone, with an estimated mortality rate of approximately 20%. There are only a small number of approved anti-fungal agents and resistance to these drugs is becoming common. We propose to isolate and characterize inhibitors of thymidylate kinase that can be developed as anti-fungal drugs. Thymidylate kinase catalyzes the phosphorylation of thymidine monophosphate to diphosphate, and it is an essential step in the production of TTP, which is required for DNA replication and repair. We propose to use high-throughput screening (HTS) of compound libraries, computational drug discovery, and Nuclear magnetic resonance (NMR) based screening of fragment libraries, to identify lead compounds. The proposal leverages expertise in thymidylate kinase enzymology and NMR (Rule), HTS (Johnston), computational chemistry (Isayev), and C. albicans biology (Mitchell).

发现用于抗真菌应用的胸苷酸激酶抑制剂抽象的：由于真菌病原体念珠菌引起的感染对人群造成了破坏。 C 仅美国，白色唱片就会导致超过40,000例侵入性念珠菌病/年，估计死亡率率约为20％。只有少数批准的抗真菌剂和对这些药物变得普遍。我们建议分离并表征胸苷酸酯激酶的抑制剂可以作为抗真菌药物开发。胸苷酸激酶催化胸苷的磷酸化单磷酸到双磷酸盐，这是TTP生产的重要步骤，这是 DNA复制和修复。我们建议使用复合库的高通量筛选（HTS），计算药物发现和基于核磁共振（NMR）的片段筛选库，以识别铅化合物。该提案利用胸苷激酶酶学方面的专业知识和NMR（规则），HTS（Johnston），计算化学（Isayev）和白色念珠菌生物学（Mitchell）。