HCV NS5B polymerase-bound conformation of a soluble sulfonamide inhibitor by 2D transferred NOESY

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 21, 2004, Pages 5333-5337

  Yannopoulos, Constantin G ^a   Xu, Ping ^b   Ni, Feng ^b   Chan, Laval ^a   Pereira, Oswy Z ^c   Reddy, T Jagadeeswar ^c   Das, Sanjoy K ^a   Poisson, Carl ^a   Nguyen Ba, Nghe ^a   Turcotte, Nathalie ^a   Proulx, Melanie ^c   Halab, Lilianne ^a   Wang, Wuyi ^c   Bédard, Jean ^a   Morin, Nicolas ^c   Hamel, Martine ^c   Nicolas, Olivier ^a   Bilimoria, Darius ^a   L'Heureux, Lucille ^a   Bethell, Richard ^c   Dionne, Gervais ^a   more..

^a ViroChem Pharma Inc   (Canada)

^b NATIONAL RESEARCH COUNCIL CANADA   (Canada)

^c Shire Canada   (Canada)

Author keywords

HCV; Inhibitor; NMR; NS5B Polymerase

Indexed keywords

ANTIVIRUS AGENT; CARBOXYLIC ACID DERIVATIVE; ENZYME INHIBITOR; RNA POLYMERASE; SULFONAMIDE INHIBITOR; THIOPHENE; UNCLASSIFIED DRUG;

ANTIVIRAL ACTIVITY; ARTICLE; DRUG CONFORMATION; DRUG IDENTIFICATION; DRUG SCREENING; DRUG TARGETING; HEPATITIS C VIRUS; NUCLEAR OVERHAUSER EFFECT; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; VIRUS REPLICATION;

ANTIVIRAL AGENTS; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PYRIDINES; RNA REPLICASE; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; THIOPHENES; VIRAL NONSTRUCTURAL PROTEINS;

HEPATITIS C VIRUS;

EID: 5344245983     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.08.018     Document Type: Article

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22. Sulfonamide 6 was studied by modeling the structure at the ionization state that could be reflected in aqueous conditions at ∼pH 7. MOE (Chemical Computing Group Inc., Montreal, Canada) was used to build and energy minimize 6 with the MMFF94s force field using a gradient of 0.01 kcal/mol Å. The resulting minimized structure was used as a starting point for generating a set of conformers obtained from the use of MOE's implemented systematic conformational searching tool. To visualize the conformational preference of 6, the first 50 lowest energy structures were examined for each of the representative 'closed' or 'open' shapes. Only the 'open' shape of 6 was observed. The average energy difference between the 1st and 50th structure was approximately 2-3 kcal/mol Å.
23. The MOE minimized structure of 6 was used as starting points for introducing distance restrains observed from the trNOE spectrum. The strongest observed H-H correlations were initially assigned to distances of 4-5 and imposed geometric constraints were set with strengths of 100. Conformations of 6 consistent with observed NOEs were generated by minimization using the MMFF94s force field and were saved as. pdb files needed for trNOE back-calculations using the trNOEPAK program. trNOEPAK is part of the ECEPP/NMR (ECEPP algorithm was originally developed in Prof. Scheraga's group at Cornell University) suite that was developed by Dr. Feng Ni group at the Biotechnology Research Institute and is currently used for conformational structure calculations/validations through comparisons of experimental and calculated transferred NOE18 spectra. The conformer. pdb file was used by the PDB2NOE program (part of ECEPP/NMR) in order to calculate the predicted transferred NOE intensities that were saved into a. noe file. The. noe was used by GFIDSJ (part of ECEPP/NMR) to generate a free-induction decay (FID) matrix (.dat file) using the calculated NOEs and the experimental chemical shifts, line widths, coupling constants and attenuation factors for all observable protons. Finally, the NMRDSP program (part of ECEPP/NMR) was used as a digital signal processing system for converting the simulated and corresponding experimental FID matrices into the NOESY spectrum. mat file. NMRVIEW 5.0.2 was used to visualize the simulated. mat spectrum seen in Figure 3. Additional references: G. Nemethy, K.D. Gibson, K.A. Palmer, C.N. Yoon, G. Paterlini, A. Zagari, S. Rumsey, and H.A. Scheraga J. Phys. Chem. 96 1992 6472
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