8AAP

Crystal structure of the PDZ tandem of syntenin in complex with compound SYNTi

8AAP の概要

• エントリーDOI: 10.2210/pdb8aap/pdb
• 分子名称: Syntenin-1, (2S)-2-[[(2S)-2-(6-bromanyl-3-oxidanylidene-1H-isoindol-2-yl)-3-[4-(5-ethanoyl-2-fluoranyl-phenyl)phenyl]propanoyl]amino]propanoic acid (3 entities in total)
• 機能のキーワード: signaling protein cell adhesion pdz domain syntenin syndecan drug design, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 37172.18

構造登録者

Feracci, M.,Barral, K. (登録日: 2022-07-01, 公開日: 2023-04-26, 最終更新日: 2024-02-07)

主引用文献

Hoffer, L.,Garcia, M.,Leblanc, R.,Feracci, M.,Betzi, S.,Ben Yaala, K.,Daulat, A.M.,Zimmermann, P.,Roche, P.,Barral, K.,Morelli, X.
Discovery of a PDZ Domain Inhibitor Targeting the Syndecan/Syntenin Protein-Protein Interaction: A Semi-Automated "Hit Identification-to-Optimization" Approach.
J.Med.Chem., 66:4633-4658, 2023

PubMed Abstract: The rapid identification of early hits by fragment-based approaches and subsequent hit-to-lead optimization represents a challenge for drug discovery. To address this challenge, we created a strategy called "DOTS" that combines molecular dynamic simulations, computer-based library design (chemoDOTS) with encoded medicinal chemistry reactions, constrained docking, and automated compound evaluation. To validate its utility, we applied our DOTS strategy to the challenging target syntenin, a PDZ domain containing protein and oncology target. Herein, we describe the creation of a "best-in-class" sub-micromolar small molecule inhibitor for the second PDZ domain of syntenin validated in cancer cell assays. Key to the success of our DOTS approach was the integration of protein conformational sampling during hit identification stage and the synthetic feasibility ranking of the designed compounds throughout the optimization process. This approach can be broadly applied to other protein targets with known 3D structures to rapidly identify and optimize compounds as chemical probes and therapeutic candidates.

PubMed: 36939673
DOI: 10.1021/acs.jmedchem.2c01569

実験手法

X-RAY DIFFRACTION (2.174 Å)