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Title: 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

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{sub 12}H{sub 19}N{sub 5}O{sub 2}S{sup 2+}{center_dot}4Cl{sup -}{center_dot}H{sub 2}O. Hydrogen bonding utilizing the H atoms of the dication is found to favor 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 indendent cations and confirm the significant energy cost of the required conformation change to the enzyme bound form. The results suggest the using crystallographically determined free ligand coordinates as starting parameters for modelling may have serious limitations.
Authors:
; ; ;
Publication Date:
OSTI Identifier:
1042285
Report Number(s):
BNL--97963-2012-JA
TRN: US201212%%696
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica Section C; Journal Volume: 66
Research Org:
BROOKHAVEN NATIONAL LABORATORY (BNL)
Sponsoring Org:
USDOE SC OFFICE OF SCIENCE (SC)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ATOMS; BIOCHEMISTRY; CHEMICAL BONDS; CATIONS; COORDINATES; DENSITY; ENZYMES; FLEXIBILITY; DENSITY FUNCTIONAL METHOD; HYDROGEN; INHIBITION; LIGANDS; PHOSPHOTRANSFERASES; SALTS