6H1I

Crystal structure of human Pirin in complex with bisamide compound 2

6H1I の概要

• エントリーDOI: 10.2210/pdb6h1i/pdb
• 分子名称: Pirin, FE (III) ION, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: transcriptional coregulator, quercetin 2, 3-dioxygenase, inhibitor, transcription
• 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: 33227.28

構造登録者

Ali, S.,Le Bihan, Y.V.,van Montfort, R.L.M. (登録日: 2018-07-11, 公開日: 2018-11-28, 最終更新日: 2024-01-17)

主引用文献

Meyers, J.,Chessum, N.E.A.,Ali, S.,Mok, N.Y.,Wilding, B.,Pasqua, A.E.,Rowlands, M.,Tucker, M.J.,Evans, L.E.,Rye, C.S.,O'Fee, L.,Le Bihan, Y.V.,Burke, R.,Carter, M.,Workman, P.,Blagg, J.,Brown, N.,van Montfort, R.L.M.,Jones, K.,Cheeseman, M.D.
Privileged Structures and Polypharmacology within and between Protein Families.
ACS Med Chem Lett, 9:1199-1204, 2018

PubMed Abstract: Polypharmacology is often a key contributor to the efficacy of a drug, but is also a potential risk. We investigated two hits discovered via a cell-based phenotypic screen, the CDK9 inhibitor CCT250006 () and the pirin ligand CCT245232 (), to establish methodology to elucidate their secondary protein targets. Using computational pocket-based analysis, we discovered intrafamily polypharmacology for our kinase inhibitor, despite little overall sequence identity. The interfamily polypharmacology of with B-Raf was used to discover a novel pirin ligand from a very small but privileged compound library despite no apparent ligand or binding site similarity. Our data demonstrates that in areas of drug discovery where intrafamily polypharmacology is often an issue, ligand dissimilarity cannot necessarily be used to assume different off-target profiles and that understanding interfamily polypharmacology will be important in the future to reduce the risk of idiopathic toxicity and in the design of screening libraries.

PubMed: 30613326
DOI: 10.1021/acsmedchemlett.8b00364

実験手法

X-RAY DIFFRACTION (1.69 Å)