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High-Throughput Fragment Docking into the BAZ2B Bromodomain: Efficient in Silico Screening for X-Ray Crystallography


Lolli, Graziano; Caflisch, Amedeo (2016). High-Throughput Fragment Docking into the BAZ2B Bromodomain: Efficient in Silico Screening for X-Ray Crystallography. ACS Chemical Biology, 11(3):800-807.

Abstract

Bromodomains are protein modules that bind to acetylated lysine side chains in histones and other proteins. The bromodomain adjacent to zinc finger domain protein 2B (BAZ2B) has been reported to be poorly druggable. Here, we screened an in-house library of 350 fragments by automatic docking to the BAZ2B bromodomain. The top 12 fragments according to the predicted binding energy were selected for experiments of soaking into apo crystals of BAZ2B which yielded the structure of the complex for four of them, which is a hit rate of 33%. Additional crystal structures were solved for BAZ2B and two scaffolds identified by analogy. For three topologically similar fragments, the crystal structures reveal binding modes with different penetration, i.e., with zero, one, and two water molecules, respectively, located between the fragment and the side chain of a conserved tyrosine (Tyr1901) in the bottom of the acetyl lysine pocket of BAZ2B. Furthermore, a remarkable stereoselectivity of the acetyl lysine pocket emerges from the crystal structures of the bromodomains of BAZ2B and SMARCA4 in complex with the chiral diol MPD (2-methyl-2,4-pentanediol).

Abstract

Bromodomains are protein modules that bind to acetylated lysine side chains in histones and other proteins. The bromodomain adjacent to zinc finger domain protein 2B (BAZ2B) has been reported to be poorly druggable. Here, we screened an in-house library of 350 fragments by automatic docking to the BAZ2B bromodomain. The top 12 fragments according to the predicted binding energy were selected for experiments of soaking into apo crystals of BAZ2B which yielded the structure of the complex for four of them, which is a hit rate of 33%. Additional crystal structures were solved for BAZ2B and two scaffolds identified by analogy. For three topologically similar fragments, the crystal structures reveal binding modes with different penetration, i.e., with zero, one, and two water molecules, respectively, located between the fragment and the side chain of a conserved tyrosine (Tyr1901) in the bottom of the acetyl lysine pocket of BAZ2B. Furthermore, a remarkable stereoselectivity of the acetyl lysine pocket emerges from the crystal structures of the bromodomains of BAZ2B and SMARCA4 in complex with the chiral diol MPD (2-methyl-2,4-pentanediol).

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:18 March 2016
Deposited On:18 Jul 2016 12:26
Last Modified:24 Jul 2016 08:10
Publisher:American Chemical Society (ACS)
ISSN:1554-8929
Publisher DOI:https://doi.org/10.1021/acschembio.5b00914
PubMed ID:26942307

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