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Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and
The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. AExpand
Structural insights into substrate specificity and the anti beta-elimination mechanism of pectate lyase.
It is clear that the catalytic calcium ions and adjacent lysine promote catalysis by acidifying the alpha-proton, facilitating its abstraction by the base. Expand
Structure of internalin C from Listeria monocytogenes.
The crystal structure of internalin C from Listeria monocytogenes has been determined at 2.0 A resolution and it is suggested that InlC may be involved in weak or transient associations with receptors, possibly being involved in binding to the surface of the bacteria or in receptor binding. Expand
Variation in the pH-dependent pre-steady-state and steady-state kinetic characteristics of cysteine-proteinase mechanism: evidence for electrostatic modulation of catalytic-site function by the
Differences in the forms of pH-dependence of the steady-state and pre-steady-state kinetic parameters support the hypothesis that, whereas for papain, the rate-determining step is the base-catalysed reaction of the acyl-enzyme intermediate with water, for actinidin it is a post-acylation conformational change required to permit release of the alcohol product and its replacement in the catalytic site by the key water molecule. Expand
Discovery of novel Jak2-Stat pathway inhibitors with extended residence time on target.
The discovery of novel inhibitors of the Jak2/Stat5 axis, the N-(1H-pyrazol-3-yl)pyrimidin-2-amino derivatives are communicated, and the rationale, synthesis and biological evaluation of these derivatives are reported. Expand
Generation of nucleophilic character in the Cys25/His159 ion pair of papain involves Trp177 but not Asp158.
Investigation of papain studies using a new series of cationic aminoalkyl 2-pyridyl disulfide time-dependent inhibitors as reactivity probes leads to the conclusion that Asp158 is not involved in the generation of nucleophilic character in the ion pair and demonstrates a key role for Trp177. Expand
Variation in aspects of cysteine proteinase catalytic mechanism deduced by spectroscopic observation of dithioester intermediates, kinetic analysis and molecular dynamics simulations.
The possibility of a slow post-acylation conformational change during catalysis by cysteine proteinases was investigated by using a new chromogenic substrate, N-acetyl-Phe-Gly methyl thionoester, four natural variants, and stopped-flow spectral analysis to monitor the pre-steady state formation of the dithioacylenzyme intermediates and their steady state hydrolysis. Expand
Structural insights into the catalytic mechanism of Trypanosoma cruzi GPXI (glutathione peroxidase-like enzyme I).
Current drug therapies against Trypanosoma cruzi, the causative agent of Chagas disease, have limited effectiveness and are highly toxic. T. cruzi-specific metabolic pathways that utilizeExpand
Evidence for 'lock and key' character in an anti-phosphonate hydrolytic antibody catalytic site augmented by non-reaction centre recognition: variation in substrate selectivity between an
The substrates used were compared by using hapten-analogous and truncated carbonate and ester substrates each containing a 4-nitrophenolate leaving group and the ways in which haptenic flexibility and IgG architecture might contribute to the differential kinetic selectivities are indicated. Expand
Improvement in hydrolytic antibody activity by change in haptenic structure from phosphate to phosphonate with retention of a common leaving-group determinant: evidence for the 'flexibility'
Two closely related immunogens differing only in the flexibility of the atomic framework around the structural motif of the haptens are used, analogous to the reaction centre of the corresponding substrates. Expand