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Bis[(1S)-1,4-azanediyl-1-(9-deazaadenin-9-yl)-1,4-dideoxy-5-methylsulfanyl-D-ribitol] tetrakis(hydrochloride) monohydrate: structure, DFT energy and ligand docking results of a potent methylthioadenosine phosphorylase inhibitor found in different molecular conformations.
Gainsford, Graeme J; Evans, Gary B; Johnston, Karen A; Seth, Michael.
Afiliación
  • Gainsford GJ; Industrial Research Limited, PO Box 31-310, Lower Hutt, New Zealand. g.gainsford@irl.cri.nz
Acta Crystallogr C ; 66(Pt 11): o527-30, 2010 Nov.
Article en En | MEDLINE | ID: mdl-21051818
The title compound, abbreviated as 5'ThiomethylImmA, is a potent inhibitor of methylthioadenosine phosphorylase [Singh et al. (2004). Biochemistry, 43, 9-18]. The synchrotron study reported here shows that the hydrochloride salt crystallizes with two independent, nearly superimposable, dications as a monohydrate with formula 2C(12)H(19)N(5)O(2)S(2+)·4Cl(-)·H(2)O. Hydrogen bonding utilizing the H atoms of the dication is found to favour certain molecular conformations in the salt, which are significantly different from those found as bound in the enzyme. Ligand docking studies starting from either of these dications or related neutral structures successfully place the conformationally revised structures in the enzyme active site but only under particular hydrogen-bonding and molecular flexibility criteria. Density functional theory calculations verify the energy similarity of the independent cations and confirm the significant energy cost of the required conformational change to the enzyme bound form. The results suggest that using crystallographically determined free ligand coordinates as starting parameters for modelling may have serious limitations.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ribitol / Purina-Nucleósido Fosforilasa / Inhibidores Enzimáticos Tipo de estudio: Prognostic_studies Idioma: En Revista: Acta Crystallogr C Año: 2010 Tipo del documento: Article País de afiliación: Nueva Zelanda Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ribitol / Purina-Nucleósido Fosforilasa / Inhibidores Enzimáticos Tipo de estudio: Prognostic_studies Idioma: En Revista: Acta Crystallogr C Año: 2010 Tipo del documento: Article País de afiliación: Nueva Zelanda Pais de publicación: Estados Unidos