5-substituted pyrimidine 1,5-anhydrohexitols: Conformational analysis and interaction with viral thymidine kinase

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 11, 1999, Pages 1563-1566

  Wouters, Johan ^a   Herdewijn, Piet ^b  

^a UNIVERSITY OF NAMUR   (Belgium)

^b REGA INSTITUTE FOR MEDICAL RESEARCH   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; PYRIMIDINE NUCLEOSIDE DERIVATIVE; THYMIDINE KINASE; VIRUS ENZYME;

ARTICLE; CONFORMATIONAL TRANSITION; CRYSTAL STRUCTURE; DRUG CONFORMATION; ENZYME BINDING; HERPES SIMPLEX VIRUS 1; HYDROGEN BOND; MOLECULAR INTERACTION; X RAY CRYSTALLOGRAPHY;

HERPES; HUMAN HERPESVIRUS 1;

EID: 0033532662     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00225-5     Document Type: Article

References (9)

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3. Ostrowski, T. et al. J. Med. Chem. 1998, 41, 4343-4353.
4. Champness, J. et al. Proteins: Struct. Funct. Genet. 1998, 32, 350-361.
5. 2. Lists of atomic coordinates, displacement parameters, structure factors and complete geometry have been deposited with the IUCr.
6. Declercq, R.; Herdewijn, P; Van Meervelt, L. Acta Cryst. 1996, C52, 1213-1215.
7. Maurinsh, Y. et al. J. Org. Chem. 1997, 62, 2861-2871.
8. Geometries corresponding to the C1 or 1C conformations of 3, 4, and 5, were constructed with the Builder program (InsightII package, MSI, San Diego) and energy minimized with the Discover program using the cvff ForceField.
9. Energy calculations on enzyme-inhibitor (5) complexes were performed with the Discover program (Amber ForceField) using the geometry of the active site observed in the crystallographic structure 2vtk (PDB code). The ADP and a structural water were retained in the calculations and their positions fixed during the minimization protocol. All residues further than 8Å from the ligand were fixed. The solvent effect was approached by using a distance dependent dielectric constant (1*r) and by retaining individual water molecules from the crystal structure, in the active site (free to move). After the inhibitor (5) had been docked into the active site (either in a C1 or 1C conformation), the complexes were energy minimized until the energy gradient dropped below 0.01 kcal/mol.