RESUMO
This report describes the first results of a rational hit-finding strategy to design novel small molecule antiinflammatory drugs targeting selectins, a family of three cellular adhesion molecules. Based on recent progress in understanding of molecular interaction between selectins and their natural ligands as well as progress in clinical development of synthetic antagonists like 1 (bimosiamose, TBC1269), this study was initiated to discover small molecule selectin antagonists with improved pharmacological properties. Considering 1 as template structure, a ligand-based approach followed by focused chemical synthesis has been applied to yield novel synthetic small molecules (MWr < 500) with a trihydroxybenzene motif, bearing neither peptidic nor glycosidic components, with nanomolar in vitro activity. Biological evaluation involves two kinds of in vitro assays, a static molecular binding assay, and a dynamic HL-60 cell attachment assay. As compared to controls, the novel compounds showed improved biological in vitro activity both under static and dynamic conditions.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Hexanos/química , Manose/análogos & derivados , Fenóis/síntese química , Selectinas/metabolismo , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Ligação Competitiva , Adesão Celular , Desenho de Fármacos , Selectina E/metabolismo , Células HL-60 , Humanos , Selectina L/metabolismo , Ligantes , Manose/química , Modelos Moleculares , Selectina-P/metabolismo , Fenóis/química , Fenóis/farmacologia , Ligação ProteicaRESUMO
Type II myosin is the molecular motor which drives contraction upon cyclic interaction with filamentous actin while consuming ATP. The contemporary crystallographic structure of the myosin subfragment-1 (S1) of myosin covers both the motor domain of the heavy chain (MHC) as well as the essential (ELC) and regulatory light chains (RLC). A part of the N-terminus of the ELC is, however, missing in the 3D-models of Type II myosin. The N-terminal domain of the ELC comprises interesting functional features since it binds to actin thus controlling myosin motor activity. For the first time, we modeled the missing 46 N-terminal amino acid of the ELC to the contemporary actin-myosin-S1 complex. We show a rod-like 91 A structure being long enough to bridge the gap between the ELC core of myosin-S1 and the appropriate binding site of the ELC on the actin filament.