Discovery of Thymidylate Kinase Inhibitors for Anti-Fungal Applications

用于抗真菌应用的胸苷酸激酶抑制剂的发现 摘要： 由真菌病原体白色念珠菌引起的感染对人类是毁灭性的。C. 仅在美国，白色念珠菌每年就引起超过40，000例侵袭性念珠菌病，估计死亡率为 率约20%。只有少数批准的抗真菌药物和耐药性 这些药物变得越来越普遍。我们建议分离和表征胸苷酸激酶的抑制剂 可以开发成抗真菌药物。胸苷酸激酶催化胸苷磷酸化 这是一个重要的步骤，在生产TTP，这是必要的， DNA复制与修复我们建议使用化合物文库的高通量筛选（HTS）， 计算药物发现和基于核磁共振（NMR）的片段筛选 图书馆，以确定铅化合物。该提案利用了胸苷酸激酶酶学方面的专业知识 NMR（Rule）、HTS（约翰斯顿）、计算化学（Isayev）和C. albicans biology（Mitchell）.

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).