ABSTRACT
In previous work [Pol-Fachin, L.; Fernandes, C. L.; Verli, H.; Carbohydr. Res.2009, 344, 491-500], we had demonstrated that GROMOS96 43a1 force field and Löwdin HF/6-31G * *-derived atomic charges, adequately represent a glycoprotein's conformational ensemble in aqueous solutions, taking as the starting geometries NMR-determined structures. Based on such data, the present work intends to evaluate the use of the main solution conformations of isolated disaccharides, to build the carbohydrate moiety of glycoproteins, for which no previous experimental information is available. The observed results suggested that the entire glycoprotein scaffold appears unable to promote major modifications in the conformational behavior of glycosidic linkages. Additionally, when compared to energy contour plots, the results support the use of solution ensembles, to refine vacuum conformations of carbohydrate databases in the assembling of glycoproteins 3D structures. Finally, such approach is applied to build a full glycosylated model for COX-1 and COX-2 enzymes.
Subject(s)
CD2 Antigens/chemistry , CD59 Antigens/chemistry , Chorionic Gonadotropin/chemistry , Computer Simulation , Glycoproteins/chemistry , Oligosaccharides/chemistry , Animals , Carbohydrate Sequence , Disaccharides/chemistry , Humans , Magnetic Resonance Spectroscopy , Mice , Models, Molecular , Molecular Conformation , Molecular Sequence Data , Polysaccharides/chemistry , Prostaglandin-Endoperoxide Synthases/chemistry , ThermodynamicsABSTRACT
A monoterpene indole alkaloid, psychollatine ( 1), was isolated from Psychotria umbellata leaves. Its structure was characterized by interpretation of spectroscopic data and by comparison of its NMR data with those of croceaine A ( 2) from Palicourea crocea. The configuration of psychollatine ( 1) was established by NOE difference and circular dichroism (CD) techniques, while its conformation was evaluated through molecular modeling studies and NMR coupling constants.
Subject(s)
Alkaloids/isolation & purification , Glycosides/isolation & purification , Indole Alkaloids/isolation & purification , Psychotria/chemistry , Alkaloids/chemistry , Brazil , Glycosides/chemistry , Indole Alkaloids/chemistry , Molecular StructureABSTRACT
Prostaglandin-H synthase exists in two isoforms, PGHS-1 and PGHS-2. PGHS-1 is present and is constitutively expressed in most cells and tissues, whereas PGHS-2 is mainly thought to mediate inflammation. Selective prostaglandin-H synthase-2 (or cyclooxygenase-2) inhibitors have been shown to be potent antiinflammatory agents with fewer side effects than currently marketed nonsteroidal antiinflammatory drugs (NSAIDs). This review addresses the main classes of the selective PGHS-2 inhibitors whose selectivity is documented by supporting PGHS-1 and PGHS-2 enzyme data. In addition, we also describe our experience in design, synthesis and pharmacological in vivo evaluation of new 1,2-benzodioxole derivatives as candidate of the selective PGHS-2 inhibitors, with special attention to molecular dynamics simulations of these derivatives attached to the active site of PGHS-2.
