MOLECULAR MODELLING AND DRUG DESIGN BY COMPUTER

一个成功的方法来模拟酶底物一直活跃 模拟分析 这包括识别和使用药效团 搜索NCI DIS 3D数据库 两种广泛使用的分子模型的验证 方案已经完成并公布。 其中一个被选中 建立NCI DIS 3D数据库。 酶结合已经表明，柔性配体，即药物， 当与活性位点结合时变形。 本过程的能源审计 建立了热力学原理。 蛋白激酶C蛋白激酶C中的药效团已经被 在NCI 3D数据库的搜索中被识别并用作目标。 这些 研究已经产生了许多作为抑制剂的化合物， 它们与佛波醇竞争PKC中的活性位点。 酪氨酸蛋白激酶底物与该酶的结合利用 酪氨酸磷酸和多达10种疏水相互作用。 等 相互作用没有得到很好的记录，因此进行了研究。 它们很弱，但无处不在，人们认为它们可能在 在酶识别底物的过程中。 其他酶活性类似物已被证明是成功的蛋白质 激酶C被应用于其他几种酶， 为控制癌症或艾滋病提供化疗靶点。 他们 包括HIV蛋白酶、HIV整合酶和端粒酶。

A successful approach to modeling of enzyme substrates has been active analog analysis. This involves identification and use of pharmacophores to search the NCI DIS 3D database. Modeling Studies Validation of two widely used molecular modeling programs has been completed and published. One of these was then selected to build the NCI DIS 3D database. Enzyme Binding It has been shown that flexible ligands, i.e. drugs, are deformed when binding to an active site. Energy audits of this process have established its thermodynamic rationale. Protein Kinase C The pharmacophore in protein kinase C has been identified and used as a target in searches of the NCI 3D database. These searches have produced numerous compounds which are inhibitors in that they compete with phorbol for the active site in PKC. Tyrosine Protein Kinase Substrate binding to this enzyme utilize a tyrosine phosphate and as many as 10 hydrophobic interactions. Such interactions are not well documented and they have therefore been studied. They are weak but ubiquitous and it is thought that they may play a role in the process by which an enzyme recognizes its substrates. Other Enzymes The active analog which has proved successful with protein kinase C is being applied to several other enzymes which are thought to offer chemotherapeutic targets for control of cancer or AIDS. They include HIV protease, HIV integrase and telomerase.