title: Virtual combinatorial syntheses and computational screening of new potential anti-herpes compounds.
abstract: 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.
authors.affiliation: Unidad de Investigación de Diseño de Fármacos y Conectividad Molecular, Facultat de Farmacia, and Departamento de Microbiología, Hospital Clínico Universitario, Universitat de València, Spain. julian@colom.combios.es
authors.forename: J V
authors.initials: JV
authors.lastname: de Julián-Ortiz
authors.forename: J
authors.initials: J
authors.lastname: Gálvez
authors.forename: C
authors.initials: C
authors.lastname: Muñoz-Collado
authors.forename: R
authors.initials: R
authors.lastname: García-Domenech
authors.forename: C
authors.initials: C
authors.lastname: Gimeno-Cardona
mesh_terms: D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D002522:Chlorocebus aethiops; D004952:Esters; D018259:Herpesvirus 1, Human / Q000737:chemistry* / Q000187:drug effects / Q000254:growth & development; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D014709:Vero Cells; D010948:Viral Plaque Assay
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D004952:Esters; D010636:Phenols