de Julián-Ortiz J V, Gálvez J, Muñoz-Collado C, García-Domenech R, Gimeno-Cardona C
Unidad de Investigación de Diseño de Fármacos y Conectividad Molecular, Facultat de Farmacia, and Departamento de Microbiología, Hospital Clínico Universitario, Universitat de València, Spain.
J Med Chem. 1999 Aug 26;42(17):3308-14. doi: 10.1021/jm981132u.
The activity of new anti-HSV-1 chemical structures, designed by virtual combinatorial chemical synthesis and selected by a computational screening, is determined by an in vitro assay. A virtual library of phenol esters and anilides was formed from two databases of building blocks: one with carbonyl fragments and the other containing both substituted phenoxy and phenylamino fragments. The library of virtually assembled compounds was computationally screened, and those compounds which were selected by our mathematical model as active ones were finally synthesized and tested. Our antiviral activity model is a "tandem" of four linear functions of topological graph-theoretical descriptors. A given chemical structure was selected as active if it satisfies every discriminant equation in that model. The final result was that five new structures were selected, synthesized, and tested: all of them demonstrated activity, and three showed appreciable anti-HSV-1 activity, with IC(50) values of 0.9 microM. The same model, applied to a database of known compounds, has identified the anti-herpes activity of the following compounds: 3,5-dimethyl-4-nitroisoxazole, nitrofurantoin, 1-(pyrrolidinocarbonylmethyl)piperazine, nebularine, cordycepin, adipic acid, thymidine, alpha-thymidine, inosine, 2, 4-diamino-6-(hydroxymethyl)pteridine, 7-(carboxymethoxy)-4-methylcoumarin, 5-methylcytidine, and others that showed less activity.
通过虚拟组合化学合成设计并经计算筛选选出的新型抗单纯疱疹病毒1型（HSV-1）化学结构的活性，由体外试验确定。从两个构建模块数据库形成了苯酚酯和苯胺的虚拟库：一个包含羰基片段，另一个包含取代苯氧基和苯氨基片段。对虚拟组装化合物库进行计算筛选，最终合成并测试那些被我们的数学模型选为活性化合物的化合物。我们的抗病毒活性模型是拓扑图论描述符的四个线性函数的“串联”。如果给定的化学结构满足该模型中的每个判别方程，则被选为活性结构。最终结果是选出了五个新结构，进行了合成和测试：所有这些结构都表现出活性，其中三个显示出明显的抗HSV-1活性，IC(50)值为0.9微摩尔。将同一模型应用于已知化合物数据库，已确定以下化合物的抗疱疹活性：3,5-二甲基-4-硝基异恶唑、呋喃妥因、1-(吡咯烷羰基甲基)哌嗪、杀结核菌素、虫草素、己二酸、胸苷、α-胸苷、肌苷、2,4-二氨基-6-(羟甲基)蝶啶、7-(羧基甲氧基)-4-甲基香豆素、5-甲基胞苷，以及其他活性较低的化合物。
