2018年2月2日 · A headgroup (here the KAc mimic is shown in orange) is virtually coupled to commercially available building blocks. The resulting library is filtered out to remove any protein-reactive functionalities and subsequently docked while maintaining key interactions of the headgroup inside the target’s binding site.

This compound (1) comprises three key sections, the KAc mimic, a tetrahydroquinoline (THQ) group that interacts with R1173 and the hydrophobic leucine, proline, and phenylalanine (LPF) shelf, and a linker that joins these two motifs (Figure 2). Here, we describe work to alter the 6-membered 3,4-dihydroquinoxalinone ring to the 4,5 ...

We demonstrate that the 3,5-dimethylisoxazole moiety is an effective KAc mimic and show how differential substitution of the 3,5-dimethylisoxazole core gives derivatives that bind with some selectivity and useful affinity to either the first bromodomain of human BRD4 [BRD4(1)] or the bromodomain of human CREBBP.

2022年12月31日 · A 1,2,4-triazole amino acid (ApmTri) was established as acetyllysine (Kac) mimic recruiting Brds of the BET family in contrast to glutamine commonly used for simulating this modification. Optimization of triazole substituents and side chain spacing allowed BET Brd recruitment to ApmTri-containing peptides with affinities similar to native ...

2016年6月6日 · These data indicate that isoxazole-containing amino acids can act as KAc mimics in the context of bromodomain recognition. The data also suggest that ligand selectivity between bromodomains can be achieved by altering interactions in the KAc binding pocket, in addition to the peptide-binding region (see the Supporting Information). Table 1.

2022年12月31日 · Lysine acetylation is a charge-neutralizing post-translational modification of proteins bound by bromodomains (Brds). A 1,2,4-triazole amino acid (ApmTri) was established as acetyllysine (Kac) mimic recruiting Brds of the BET family in contrast to glutamine commonly used for simulating this modification.

2016年3月1日 · Acetylated lysine residues (Kac) of histones are selectively recognised by a conserved protein interaction module known as a bromodomain (BRD) [1], [2]. BRD-containing proteins subsequently induce changes to gene expression through catalytic domains or through anchoring other proteins to the chromatin [3] .

2014年6月6日 · An X-ray crystal structure of (R)-1 bound to the CREBBP bromodomain revealed that the dihydroquinoxalinone was acting as the KAc mimic (Figure 2 A). The amide of the dihydroquinoxalinone formed two hydrogen bonds with N1168, and the methyl group resided at the base of the KAc-binding pocket (Figure 2 A ).

2023年3月13日 · A 1,2,4-triazole amino acid (ApmTri) was established as acetyllysine (Kac) mimic recruiting Brds of the BET family in contrast to glutamine commonly used for simulating this modification. Optimization of triazole substituents and side chain spacing allowed BET Brd recruitment to ApmTri-containing peptides with affinities similar to native ...

2019年12月12日 · Our previous reports have showed that 7-methylimidazo[1,5-a]pyrazin-8(7H)-one of 28 exhibited the strong inhibition potency, acting as KAc mimic. 31−33 The docking process was utilized to elaborate the interaction between the moiety and BRD4 protein.