RESUMEN
We report on a hit generation and hit-to-lead program of a novel class of glucokinase activators (GKAs). Hit compounds, activators at low glucose concentration only were identified by vHTS. Scaffold modification reliably afforded activators also at high substrate level. Potency was increased by introduction of a hydrogen bond acceptor as proposed by molecular docking. Replacement of the initial alkylene linkers with a rigid 1,2-phenylene motif followed by further studies eventually furnished a series of potent lead compounds exhibiting steep SAR.
Asunto(s)
Descubrimiento de Drogas , Activadores de Enzimas/farmacología , Glucoquinasa/metabolismo , Regulación Alostérica/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Activadores de Enzimas/síntesis química , Activadores de Enzimas/química , Enlace de Hidrógeno , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Using a vHTS based on a pharmacophore alignment on known beta3-adrenoceptor ligands, a set of intriguing beta-adrenoceptor ligands was identified, optimization of which resulted in a selective and potent human beta2-AR antagonist.
Asunto(s)
Receptores Adrenérgicos beta/metabolismo , Semivida , Humanos , Enlace de Hidrógeno , Ligandos , Modelos MolecularesRESUMEN
Over the past decade investigations of human mitochondrial DNA (mtDNA) have considerably contributed to our knowledge about human evolution and migration. The genome of the Icelandic population is of special interest since Iceland has been genetically isolated for centuries. The sequence of the hypervariable regions HVS-I and HVS-II of the mtDNA control region was generated for 100 Icelandic individuals. A total of 75 different mtDNA sequences were observed, of which 19 sequences were shared by more than one individual, 16 sequences were shared by two individuals and two sequences were shared by three individuals; the most frequent haplotype (16129 A, 16239 T, 00263 G and 00315.1 C) was found six times. Both the genetic diversity (0.9925+/-0.0031) and the average number of pairwise nucleotide differences (7.371) were comparable with most of the other European populations. However, we found a smaller number of distinct mitochondrial lineages, suggesting that founder effects and genetic drift may have exerted a visible influence on the Icelandic genetic diversity. We compared these data with 1400 other European sequences from the D-Loop-BASE database. The paper discusses the evolutionary relationship between Icelandic and Central European mtDNA under due consideration of the historical context. Finally, our study has been aimed at increasing the number of mtDNA sequences available throughout the world and contributing to human genome investigations.
Asunto(s)
ADN Mitocondrial/análisis , Variación Genética , Genética de Población , Haplotipos , Análisis de Secuencia de ADN , Dermatoglifia del ADN , Humanos , IslandiaRESUMEN
Based on a pharmacophore alignment on a 5-HT(6) ligand applying 4SCan technology, a new lead series was identified and further structurally investigated. K(i)s down to 8 nM were achieved.
Asunto(s)
Compuestos de Anilina/química , Simulación por Computador , Piperazinas/química , Receptores de Serotonina/química , Sulfonamidas/química , Compuestos de Anilina/farmacología , Diseño de Fármacos , Humanos , Indoles/química , Indoles/farmacología , Ligandos , Modelos Moleculares , Estructura Molecular , Piperazina , Piperazinas/farmacología , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Programas Informáticos , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
Based on a pharmacophore alignment on known non-competitive mGluR5 inhibitors applying 4SCan technology, a new lead series was identified and further structurally investigated. K(i)'s as low as around 100 nM were achieved.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Antagonistas de Aminoácidos Excitadores/química , Receptor del Glutamato Metabotropico 5 , Relación Estructura-ActividadRESUMEN
The high throughput in silico screening of a virtual library into the structure of the P. falciparum lactate dehydrogenase (LDH) with the 4SCan technology yielded a series of biphenyl urea compounds. These were chemically optimized to a new structural class of potent antimalarial agents. The compounds did not inhibit plasmodium LDH enough to fully explain their potency. Therefore we conclude that an unknown mode of action may be the cause of the antimalarial activity.