RESUMEN
BAZ2A is an epigenetic regulator affecting transcription of ribosomal RNA. It is overexpressed in aggressive and recurrent prostate cancer, promoting cellular migration. Its bromodomain is characterized by a shallow and difficult-to-drug pocket. Here, we describe a structure-based fragment-growing campaign for the identification of ligands of the BAZ2A bromodomain. By combining docking, competition binding assays, and protein crystallography, we have extensively explored the interactions of the ligands with the rim of the binding pocket, and in particular ionic interactions with the side chain of Glu1820, which is unique to BAZ2A. We present 23 high-resolution crystal structures of the holo BAZ2A bromodomain and analyze common bromodomain/ligand motifs and favorable intraligand interactions. Binding of some of the compounds is enantiospecific, with affinity in the low micromolar range. The most potent ligand has an equilibrium dissociation constant of 7 µM and a good selectivity over the paralog BAZ2B bromodomain.
RESUMEN
Small molecule ligand binding to the ATAD2 bromodomain is investigated here through the synergistic combination of molecular dynamics and protein crystallography. A previously unexplored conformation of the binding pocket upon rearrangement of the gatekeeper residue Ile1074 has been found. Further, our investigations reveal how minor structural differences in the ligands result in binding with different plasticity of the ZA loop for this difficult-to-drug bromodomain.
RESUMEN
We analyze 20 crystal structures of complexes between the CBP bromodomain and small-molecule ligands that belong to eight different chemotypes identified by docking. The binding motif of the moiety that mimics the natural ligand (acetylated side chain of lysine) at the bottom of the binding pocket is conserved. In stark contrast, the rest of the ligands form different interactions with different side chains and backbone polar groups on the outer rim of the binding pocket. Hydrogen bonds are direct or water-bridged. van der Waals contacts are optimized by rotations of hydrophobic side chains and a slight inward displacement of the ZA loop. Rare types of interactions are observed for some of the ligands.
RESUMEN
Expanding the chemical space and simultaneously ensuring synthetic accessibility is of upmost importance, not only for the discovery of effective binders for novel protein classes but, more importantly, for the development of compounds against hard-to-drug proteins. Here, we present AutoCouple, a de novo approach to computational ligand design focused on the diversity-oriented generation of chemical entities via virtual couplings. In a benchmark application, chemically diverse compounds with low-nanomolar potency for the CBP bromodomain and high selectivity against the BRD4(1) bromodomain were achieved by the synthesis of about 50 derivatives of the original fragment. The binding mode was confirmed by X-ray crystallography, target engagement in cells was demonstrated, and antiproliferative activity was showcased in three cancer cell lines. These results reveal AutoCouple as a useful in silico coupling method to expand the chemical space in hit optimization campaigns resulting in potent, selective, and cell permeable bromodomain ligands.
RESUMEN
N-heterocyclic carbene (NHC) supported coinage metal cations proved to react in the gas phase with the electron-rich cis-1,2-dimethoxycyclopropane. Upon Collision Induced Dissociation (CID), several spectrometric fragment-ion signals were observed, one corresponding to the recovery of the bare cation IMes-M(+) (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) and the second to the methoxymethylidene metal complex IMes-M-[HCOCH3](+). The gold and copper complexes appear to stabilize the carbene sufficiently enough to promote the latter channel. On the contrary, the silver complex binds weakly to the methoxymethylidene moiety as observed by the predominance of the bare cation IMes-M(+) channel. Density Functional Theory (DFT) investigations of the Potential Energy Surface and Bond Energy Decomposition Analyses provided results that correlate well with the experimental data. In the case of the bare cation channel, two distinct reaction pathways were found: a straightforward decoordination of the cyclopropane and a cationic rearrangement of the three-membered ring into a dimethoxypropylene isomer before dissociation. However, for the abstraction of the methoxymethylidene moiety by the metal cation, only one pathway was found. In analogy to earlier studies by other groups, we found the trend Au > Cu > Ag for the metal-carbene bond strength.
RESUMEN
The gas-phase cyclopropanation and apparent metathesis reactivity of ligand-supported gold arylidenes with electron-rich olefins is explained by quantum-chemical calculations. A deep potential minimum corresponding to a metal-bound cyclopropane adduct is in agreement with the measured absolute energies of the cyclopropanation and metathesis channels and is also consistent with previously reported electronic effects of arylidenes and supporting phosphorus ylid ligands on the product ratios. In the gas phase, the rate-determining step for the cyclopropanation is dissociation of the Lewis-acidic metal fragment, whereas the metathesis pathway features several rate-limiting transition states that are close in energy to the final product dissociation and hence contribute to the overall reaction rate. Importantly, the presented potential energy surface also accounts for the recently reported gold-catalyzed solution-phase retro-cyclopropanation reactivity.
RESUMEN
We report experimental and computational evidence that cationic N-heterocyclic carbene gold complexes with electron-rich cyclopropanes rearrange to produce Fischer gold carbene complexes in the gas phase, in analogy to long-known condensed-phase rearrangements of protonated cyclopropanes. Our results help to generalize the relationship between Lewis-acidic metal complexes of cyclopropanes, metallacyclobutanes and metal carbenes.