Inhibition of human rhinovirus 3C protease by homophthalimides

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 12, 1997, Pages 1589-1594

  Jungheim, Louis N ^a   Cohen, Jeffrey D ^a   Johnson, Robert B ^a   Villarreal, Elcira C ^a   Wakulchik, Mark ^a   Loncharich, Richard J ^a   Wang, Q May ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HOMOPHTHALIMIDE DERIVATIVE; ISOQUINOLINE DERIVATIVE; PROTEINASE; UNCLASSIFIED DRUG;

ANTIVIRAL ACTIVITY; ARTICLE; DRUG SYNTHESIS; ENZYME BINDING; ENZYME INHIBITION; HUMAN RHINOVIRUS; IN VITRO STUDY; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; MOLECULAR MODEL; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; QUANTITATIVE STRUCTURE ACTIVITY RELATION;

EID: 0030990054     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00268-0     Document Type: Article

References (20)

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14. 1H NMR, MS).
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16. pro accounts for the finding that weak inhibitors such as 2a appeared active in the blind screen.
17. Molecular modeling experiments were performed with the CHARMM program (Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States, D. J.; Swaminathan, S.; Karplus, M. J. Comp. Chem. 1983, 4, 187). Random conformations of the inhibitors were docked within the active site and the complexes were subsequently subjected to repeated short term molecular dynamics and energy minimization. The resulting structures were energy minimized to zero energy gradient and analyzed.
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19. pro (20 μM) was incubated for 6 h with the specified compounds (125-130 μM) or DMSO as a control. The treated enzyme samples were then diluted 1:1 with 1% acetic acid in acetonitrile (v/v) and continuously infused into the interface at a rate of 10-20 mL/min. using a syringe pump. MS spectra were collected over a range of 1000-2000 u at 0.1 u intervals with a dwell time of 1 msec per interval. A total of 10-20 scans were averaged to yield the final spectrum.
20. 50), percent inhibition of the virus yield was plotted against the logarithm of the concentration of the compound.