8AHI

PAC-FragmentDEL: Photoactivated covalent capture of DNA encoded fragments for hit discovery

8AHI の概要

• エントリーDOI: 10.2210/pdb8ahi/pdb
• 分子名称: Serine/threonine-protein kinase PAK 4, ~{N}-methyl-1,3-benzothiazole-6-carboxamide (3 entities in total)
• 機能のキーワード: protein kinase, pak4, atp-binding, transferase, technology
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33572.98

構造登録者

Baker, L.M.,Murray, J.B.,Hubbard, R.E. (登録日: 2022-07-21, 公開日: 2022-09-14, 最終更新日: 2024-11-20)

主引用文献

Ma, H.,Murray, J.B.,Luo, H.,Cheng, X.,Chen, Q.,Song, C.,Duan, C.,Tan, P.,Zhang, L.,Liu, J.,Morgan, B.A.,Li, J.,Wan, J.,Baker, L.M.,Finnie, W.,Guetzoyan, L.,Harris, R.,Hendrickson, N.,Matassova, N.,Simmonite, H.,Smith, J.,Hubbard, R.E.,Liu, G.
PAC-FragmentDEL - photoactivated covalent capture of DNA-encoded fragments for hit discovery.
Rsc Med Chem, 13:1341-1349, 2022

PubMed Abstract: We describe a novel approach for screening fragments against a protein that combines the sensitivity of DNA-encoded library technology with the ability of fragments to explore what will bind. Each of the members of the library consists of a fragment which is linked to a photoactivatable diazirine moiety. Split and pool synthesis combines each fragment with a set of linkers with the version of the library reported here containing some 70k different compounds, each with an individual DNA code. Incubation of the library with a protein sample is followed by photoactivation, washing and subsequent PCR and sequencing which allows the individual fragment hits to be identified. We illustrate how the approach allows successful hit fragment identification using only microgram quantities of material for two targets. PAK4 is a kinase for which conventional fragment screening has generated many advance leads. The as yet undrugged target, 2-epimerase, presents a more challenging active site for identification of hit compounds. In both cases, PAC-FragmentDEL identified fragments validated as hits by ligand-observed NMR measurements and crystal structure determination of off-DNA sample binding to the proteins.

PubMed: 36426238
DOI: 10.1039/d2md00197g

実験手法

X-RAY DIFFRACTION (2.69 Å)