RESUMO
This editorial discusses the foundation of aspects of computational chemistry and is a tribute to Peter Goodford, one of those founders, who recently passed away. Several colleagues describe Professor Goodford's work and the person himself.
Assuntos
Química Computacional/história , Cristalografia por Raios X/história , História do Século XX , História do Século XXI , HumanosRESUMO
Inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) show promise as drugs to treat metabolic disease and CNS disorders such as cognitive impairment. A series of 1,5-substituted 1H-tetrazole 11beta-HSD1 inhibitors has been discovered and chemically modified. Compounds are selective for 11beta-HSD1 over 11beta-HSD2 and possess good cellular potency in human and murine 11beta-HSD1 assays. A range of in vitro stabilities are observed in human liver microsome assays.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Tetrazóis/farmacologia , Animais , Humanos , Camundongos , Modelos MolecularesRESUMO
A highly efficient, practical and flexible two-step asymmetric synthesis of the beta(2)-selective beta-blocker ICI 118,551 is reported, allowing an unambiguous determination of the dependency of biological activity with optical activity, revealing the S,S-enantiomer to be the most potent.
Assuntos
Antagonistas Adrenérgicos beta/síntese química , Propanolaminas/síntese química , Antagonistas de Receptores Adrenérgicos beta 1 , Antagonistas de Receptores Adrenérgicos beta 2 , Antagonistas Adrenérgicos beta/química , Cristalografia por Raios X , Conformação Molecular , Propanolaminas/química , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , EstereoisomerismoRESUMO
A series of adamantyl amide 11beta-HSD1 inhibitors has been discovered and chemically modified. Selected compounds are selective for 11beta-HSD1 over 11beta-HSD2 and possess excellent cellular potency in human and murine 11beta-HSD1 assays. Good pharmacodynamic characteristics are observed in ex vivo assays.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/farmacologia , Amidas/farmacologia , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , Adamantano/química , Amidas/química , Animais , Inibidores Enzimáticos/química , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The paper describes the generation of four types of three-dimensional molecular field descriptors or 'field points' as extrema of electrostatic, steric, and hydrophobic fields. These field points are used to define the properties necessary for a molecule to bind in a characteristic way into a specified active site. The hypothesis is that compounds showing a similar field point pattern are likely to bind at the same target site regardless of structure. The methodology to test this idea is illustrated using HIV NNRTI and thrombin ligands and validated across seven other targets. From the in silico comparisons of field point overlays, the experimentally observed binding poses of these ligands in their respective sites can be reproduced from pairwise comparisons.