1996
DOI: 10.1021/jm960603e
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Design, Synthesis, and Evaluation of Nonpeptidic Inhibitors of Human Rhinovirus 3C Protease

Abstract: The design, synthesis, and biological evaluation of reversible, nonpeptidic inhibitors of human rhinovirus (HRV) 3C protease (3CP) are reported. A novel series of 2,3-dioxindoles (isatins) were designed that utilized a combination of protein structure-based drug design, molecular modeling, and structure-activity relationship (SAR). The C-2 carbonyl of isatin was envisioned to react in the active site of HRV 3CP with the cysteine responsible for catalytic proteolysis, thus forming a stabilized transition state … Show more

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Cited by 137 publications
(135 citation statements)
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“…Indeed, we showed previously that 2,3-dioxindole inhibitors (see Fig. 1, compound II) form stable tetrahedral adducts with 3C pro- tease in which the O3 oxygen is stabilized in just this manner (18). However, compound I binds in a non-transition-state conformation with the oxygen of the hemithioacetal stabilized by hydrogen bonding to N2 of His-40.…”
Section: Inhibitors Of 3c Protease and The Issue Of Serotypic Diversimentioning
confidence: 91%
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“…Indeed, we showed previously that 2,3-dioxindole inhibitors (see Fig. 1, compound II) form stable tetrahedral adducts with 3C pro- tease in which the O3 oxygen is stabilized in just this manner (18). However, compound I binds in a non-transition-state conformation with the oxygen of the hemithioacetal stabilized by hydrogen bonding to N2 of His-40.…”
Section: Inhibitors Of 3c Protease and The Issue Of Serotypic Diversimentioning
confidence: 91%
“…When elaborated with substituents providing recognition in the S1 and S2 specificity pockets of 3C protease, inhibitors with low nanomolar K i were obtained. An x-ray cocrystal structure of compound II revealed covalent attachment of Cys-147 to the electrophilic center (C2) with the carboxamide and benzothiophene groups positioned as expected in the S1 and S2 pockets (18). Unfortunately, all isatin inhibitors tested were devoid of antiviral activity and͞or were toxic, properties most probably attributable to their high electrophilic reactivity.…”
Section: Inhibitors Of 3c Protease and The Issue Of Serotypic Diversimentioning
confidence: 91%
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“…Briefly, the inactivation constant (K obs /[I]) was determined using a continuous fluorometric assay and various concentrations of inhibitor. The initial data were analyzed with the first order rate kinetic equation (in ENZFIT-TER), and the resulting rate constants were then plotted against inhibitor concentration as a linear regression (30,31). Specificity assays against a variety of serine and cysteine proteases (except calpain) were done in a 96-well plate continuous spectrophotometric format under established conditions with enzyme and compound incubated for 10 min prior to starting the reaction.…”
Section: Compounds (E)-(s)-4-((s)-2-{3-[(5-mentioning
confidence: 99%
“…Schiff and Mannich bases of isatin were reported to possess antibacterial 10 , antifungal 11 , antiviral 12 , anti-HIV 13 , anti protozoal 14 , antiviral 15 and anticancer 16 . Within the context of enzyme inhibitors, isatin derivatives have found recent applications in the inhibition of cysteine and serine proteases 17,18 . Recently, isatin hydrazone derivative complexes of Cu(II), Ni(II) and Zn(II) have been reported to exhibit potential antitumour activity evaluated on human leukemic cells 19 .…”
Section: Introductionmentioning
confidence: 99%