RESUMEN
A novel approach to the synthesis of substituted 5-amino- and 3-amino-1,2,4-thiadiazoles beginning from a common precursor has been achieved. Derivatization by palladium-catalyzed Suzuki-Miyaura coupling enables the rapid preparation of analogs around this pharmaceutically relevant core. FMO calculations rationalize the observed chemoselectivity for coupling at chlorine.
Asunto(s)
Paladio/química , Tiadiazoles/síntesis química , Catálisis , Técnicas Químicas Combinatorias , Hidrocarburos Bromados/síntesis química , Hidrocarburos Bromados/química , Estructura Molecular , Tiadiazoles/químicaRESUMEN
In using computational tools for library design it is necessary to understand the performance and limitations of available methods. This letter reports systematic comparisons of applying ligand-based and structure-based tools across therapeutic project-derived data sets. Included are assessments of performance in real-world iterative design applications and the utility of target structural information. The results suggest that combining screening and target structure information is robust; further, a well-designed screening library can compensate for lacking structural information.
Asunto(s)
Técnicas Químicas Combinatorias , Bases de Datos Factuales , Programas Informáticos , Quinasas CDC2-CDC28/antagonistas & inhibidores , Quinasas CDC2-CDC28/química , Quinasa 2 Dependiente de la Ciclina , Diseño de Fármacos , Inhibidores Enzimáticos/química , Ligandos , Relación Estructura-Actividad Cuantitativa , Serina Endopeptidasas/químicaRESUMEN
Protein structural information is combined with combinatorial library design in the following protocol. Active site maps are generated from protein structures. All possible 2-, 3- and 4-point pharmacophores are enumerated from the active site map and encoded as bit strings. The pharmacophores define a design space that can be used to select compounds using an informative library design tool. The method was evaluated against a collection of compounds assayed previously against a cyclin-dependent kinase target, CDK-2, starting with 23 X-ray co-crystal structures. Performance was assessed based on the number of active scaffolds selected after four rounds of iterative informative library design. The method selects compounds from 12 out of the 15 active scaffolds from the CDK-2 library and outperforms a two-dimensional similarity search and docking calculations.
Asunto(s)
Quinasas CDC2-CDC28 , Química Farmacéutica/métodos , Técnicas Químicas Combinatorias , Diseño de Fármacos , Algoritmos , Sitios de Unión , Cristalografía por Rayos X , Quinasa 2 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes/química , Quinasas Ciclina-Dependientes/metabolismo , Bases de Datos Factuales , Bibliotecas , Estructura Molecular , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Relación Estructura-Actividad Cuantitativa , Programas Informáticos , Relación Estructura-ActividadRESUMEN
A novel shape-feature-based computational method is described and used to rapidly filter compound libraries. The computational model, built using three-dimensional conformations of active and inactive molecules, consists of a collection of whole molecule shapes and chemical feature positions that are ranked according to their correlation with activity. A small ensemble of these shapes and features is used to filter virtual compound libraries. The method is applied to two thrombin data sets and is shown to be efficient in identifying novel scaffolds with enhanced hit rates.
