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EZH2 (enhancer of zeste homologue 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of lysine 27 of histone H3 (H3K27). ...Dysregulation of EZH2 activity is associated with several human cancers and therefore EZH2 inhibition has emerged as a promising therapeutic target. Several small molecule EZH2 inhibitors with different chemotypes have been reported in the literature, many of which use a bicyclic heteroaryl core. Herein, we report the design and synthesis of EZH2 inhibitors containing an indoline core. Partial saturation of an indole to an indoline provided lead compounds with nanomolar activity against EZH2, while also improving solubility and oxidative metabolic stability.
An all-atom model for benzene is reported and tested largely in Monte Carlo simulations of pure liquid benzene, benzene in dilute aqueous solution, and the benzene dimer in water and chloroform. Free ...energy profiles were obtained for the association of the benzene dimer in liquid benzene, water, and chloroform that characterize the energetics for this prototypical interaction between arenes in solution. In all cases a contact dimer with a ring center-ring center separation of ca. 5.5 {angstrom} is found to be energetically preferred. Face-to-face stacked structures are net repulsive. However, gas-phase optimizations indicate that shifted, stacked structures become increasingly favorable with increasing arene size. Comparisons are made with key experimental data, including the free energy of hydration of benzene and the association constant, K{sub a}, for the benzene dimer in water.
We have identified and synthesized a series of thiophene containing inhibitors of kinesin spindle protein. SAR studies led to the synthesis of
33, which was co-crystallized with KSP and determined to ...bind to an allosteric pocket previously described for other known KSP inhibitors.
We have identified and synthesized a series of thiophene containing inhibitors of kinesin spindle protein. SAR studies led to the synthesis of
33, which was co-crystallized with KSP and determined to bind to an allosteric pocket previously described for other known KSP inhibitors.
Monte Carlo computer simulations have been performed in conjunction with free-energy perturbation calculations to determine the relative binding constants of four benzamidine inhibitors with trypsin. ...The protein backbone was constrained in the simulations, but sampling of the side chains was allowed. The calculated free energies are very precise and are shown to yield closed thermodynamic cycles. The calculations correctly predict p-aminobenzamidine to be the strongest inhibitor and give relative free energies of binding for p-methyl- and p-chlorobenzamidine in excellent agreement with experiment. The predicted overly weak binding of the parent benzamidine is most likely due to a deficiency in the partial charges. The relative binding affinities are justified in terms of bulk-solvation arguments whereby the more polar inhibitors are preferentially stabilized in water. The calculations demonstrate that Monte Carlo computer simulations can be used to determine accurate and precise relative binding constants for protein systems.
Anaphylatoxin C5a is a potent inflammatory mediator associated with pathogenesis and progression of several inflammation-associated disorders. Small molecule C5a receptor (C5aR) antagonist ...development is hampered by species-specific receptor biology and the associated inability to use standard rat and mouse in vivo models. Gerbil is one rodent species reportedly responsive to small molecule C5aR antagonists with human C5aR affinity. We report the identification of the gerbil C5aR cDNA using a degenerate primer PCR cloning strategy. The nucleotide sequence revealed an open reading frame encoding a 347-amino acid protein. The cloned receptor (expressed in Sf9 cells) bound recombinant human C5a with nanomolar affinity. Alignment of the gerbil C5aR sequence with those from other species showed that a Trp residue in transmembrane domain V is the only transmembrane domain amino acid unique to small molecule C5aR antagonist-responsive species (i.e. gerbil, human, and non-human primate). Site-directed mutagenesis was used to generate human and mouse C5aRs with a residue exchange of this Trp residue. Mutation of Trp to Leu in human C5aR completely eliminated small molecule antagonist-receptor interaction. In contrast, mutation of Leu to Trp in mouse C5aR enabled small molecule antagonist-receptor interaction. This crucial Trp residue is located deeper within transmembrane domain V than residues reportedly involved in C5a- and cyclic peptide C5a antagonist-receptor interaction, suggesting a novel interaction site(s) for small molecule antagonists. These data provide insight into the basis for small molecule antagonist species selectivity and further define sites critical for C5aR activation and function.
The hypothesis that the relative energies of anchimerically assisted solvolysis reactions are very similar in the gas phase and in solution, implying that relative carbocation stabilities are the ...same in both media, is probed in the present work by including solvent effects in the energy computations. We chose water as our solvent since we expect the difference in solvation energies to be large in highly polar media. Results show that the classical 2-norbornyl cation (2) is not significantly more stabilized in aqueous solution than the nonclassical ion (1). Thus both the gas phase ab initio computations and Monte Carlo solution simulation come to the same result. In less polar solvents, the solvation energies are expected to be even more similar. Our results confirm that the nonclassical form 1 of the 2-norbornyl cation is the only stable form in the gas phase and in solution. The classical form 2 is unlikely to be involved in solvolysis reactions. As a consequence, the differences in rates of solvolysis for 2-exo and 2-endo norbornyl derivatives can only be explained in terms of the differences in the exo vs endo transition states. 15 refs., 1 fig.
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