COMPUTER-AIDED DRUG DESIGN/DISCOVERY FOR CHAGAS DISEASE

针对恰加斯病的计算机辅助药物设计/发现

• 批准号: 6235216
• 负责人: FRED E COHEN
• 金额: $ 15.37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6235216
• 关键词: Trypanosoma cruzi; X ray crystallography; antiprotozoal agents; chemical information system; chemical stability; computer simulation; cysteine endopeptidases; drug design /synthesis /production; molecular dynamics; protease inhibitor; structural biology; trypanosomiasis

A program for the development of new agents to treat T. Cruzi, the parasite responsible for Chagas' Disease, is presented. Cruzain, a cysteine protease is identified as a target for a structure based drug discovery program. Models of the three-dimensional structure of cruzain built by homology to other cysteine proteases of known structure and the recently determined x-ray structure of cruzain will be used as a template for the in compuo screening of the fine chemicals directory, a data base of about 70,000 purchaseable small molecules. Compounds selected in this computer based screen will be characterized experimentally. We expect that 2-10% of the computer selected inhibitors will be active experimentally against the enzyme at concentrations less than 100 microM. Already, we have identified cruzain inhibitors active at 2-4 microM concentrations. Free energy perturbation calculations will be used to help the synthetic chemists develop more active compounds. Some will be based on the non-peptidic leads derived from the computer data base searches, while others will be analogs of the nanomolar mechanistic inhibitor Z-Phe-Arg-FMK (Z= carbobenzoxy, FMK = fluoromethyl ketone) that have been altered to eliminate peptide character. A close interaction between molecular biology, structural biology, synthetic chemistry and computational chemistry will be used to exploit a structure based drug design cycle.

一个开发治疗T. Cruzi的新药的项目