8AAO

Crystal structure of the PDZ tandem of syntenin in complex with compound 95

Summary for 8AAO

• Entry DOI: 10.2210/pdb8aao/pdb
• Descriptor: Syntenin-1, (2~{S})-2-[[(2~{S})-3-[4-(5-ethanoyl-2-fluoranyl-phenyl)phenyl]-2-(3-oxidanylidene-1~{H}-isoindol-2-yl)propanoyl]amino]propanoic acid (3 entities in total)
• Functional Keywords: signaling protein cell adhesion pdz domain syntenin syndecan drug design, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 37014.39

Authors

Feracci, M.,Barral, K. (deposition date: 2022-07-01, release date: 2023-04-26, Last modification date: 2024-02-07)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.469 Å)