“…The homology is evident in the overlay of progesterone and the nitrile-inhibitor 76 in the progesterone receptor site (Figure 21). 175 The nitrile nitrogen occupies virtually the same position as the carbonyl oxygen of progesterone and engages in the same polar interactions.…”
Section: Resultsmentioning
confidence: 99%
“… 21 Nitrile inhibitor 76 and progesterone ( 10 ) overlay. Reprinted with permission from Bioorganic and Medicinal Chemistry Letters . Copyright 2009 Elsevier.…”
“…The homology is evident in the overlay of progesterone and the nitrile-inhibitor 76 in the progesterone receptor site (Figure 21). 175 The nitrile nitrogen occupies virtually the same position as the carbonyl oxygen of progesterone and engages in the same polar interactions.…”
Section: Resultsmentioning
confidence: 99%
“… 21 Nitrile inhibitor 76 and progesterone ( 10 ) overlay. Reprinted with permission from Bioorganic and Medicinal Chemistry Letters . Copyright 2009 Elsevier.…”
“…Several crystal structures show hydrogen bonding between the nitrile nitrogen and amino acids or water-mediated interactions with protein backbones . In other cases, the strong dipole facilitates polar interactions, in which the nitrile acts as a hydroxyl or carboxyl isostere . Most nitrile-containing pharmaceuticals are aromatics with aliphatic-, alkene-, and nitrogen-bound nitriles (cyanamides) being progressively less frequent.…”
Here, we report on a mechanistic investigation based on DFT calculations and kinetic measures aimed at determining the energetics related to the cysteine nucleophilic attack on nitrile-carrying compounds. Activation energies were found to correlate well with experimental kinetic measures of reactivity with cysteine in phosphate buffer. The agreement between computations and experiments points to this DFT-based approach as a tool for predicting both nitrile reactivity toward cysteines and the toxicity of nitriles as electrophile agents.
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