MOLECULAR MODELING AND DRUG DESIGN BY COMPUTER

计算机分子建模和药物设计

• 批准号: 2463717
• 负责人: G W MILNE
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2463717
• 关键词: antiAIDS agent; antineoplastics; chemical information system; chemical structure function; computer simulation; drug design /synthesis /production; endopeptidases; enzyme inhibitors; human immunodeficiency virus; integrase; protein kinase C

Compounds that bind to an enzyme generally contain a pharmacophore that is specific for the enzyme. The geometric criteria of a pharmacophore, deduced from the structure of known substrates, has been used to design and discover alternative substrates, which can behave as competitive inhibitors of the enzyme. Such inhibitors are lead drugs which can be developed into drug candidates by chemical modification, to modify solubility or toxicity for example. Methods have been developed to conduct 3D searches through structural databases for compounds with specific geometries. Such searches routinely produce compounds which behave as enzyme inhibitors. In an alternative approach, computer programs which can design chemical structures having predetermined geometric characteristics are being used to design enzyme inhibitors. Some 30 inhibitors or protein kinase C have been developed in this way. These inhibitors have an optimum lipophilicity and the nature of their binding to the enzyme has been characterized structurally. Typically between 5 and 12 hydrogen bonds, corresponding to binding energies of 5-25 kcal/mol are involved. Non-peptidic, competitive inhibitors of HIV protease have also been developed by these methods. These occupy the active site of the enzyme, forming hydrogen bonds to Asp25, Asp25', Ile50 and Ile50' in the enzyme dimer. Likewise, numerous inhibitors of HIV integrase have been identified. Such inhibitors are all active at the nM-mu M level in enzyme assays: a small proportion of the enzymatically active compounds are also active in cellular assays and these are being pursued as lead drug candidates.

与酶结合的化合物通常包含一个药效团， 是这种酶所特有的。药效团的几何标准， 从已知衬底的结构推导出来的，已被用于设计 并发现替代底物，这些底物可以作为竞争对手 酶的抑制剂。这类抑制剂是先导药物，可以 通过化学修饰开发成候选药物，以进行修饰 例如，溶解或毒性。已经开发出了一些方法来 通过结构数据库对化合物进行3D搜索 特定的几何图形。这样的搜索通常产生的化合物 起到酶抑制剂的作用。在另一种方法中，计算机 可以设计具有预定的化学结构的程序 几何特性正被用来设计酶抑制剂。 用这种方法已经开发出了大约30种抑制剂或蛋白激酶C。 这些抑制剂具有最佳的亲脂性和它们的性质 与该酶的结合已经从结构上进行了表征。通常 在5到12个氢键之间，对应于 5-25千卡/摩尔。非肽类竞争性抑制物 HIV蛋白水解酶也是通过这些方法被开发出来的。这些人占据了 酶的活性部位，与Asp25，Asp25‘， 酶二聚体中的Ile50和Ile50‘。同样，许多抑制剂 人类免疫缺陷病毒整合酶的基因已被鉴定。这些抑制剂都是活性的。 在酶分析的NM-MU-M水平上：一小部分 酶活性化合物在细胞分析中也是活性的， 这些都是作为主要候选药物的研究对象。