8aai | pdb_00008aai
Crystal structure of the PDZ tandem of syntenin in complex with fragment E5
Structural highlights
FunctionSDCB1_HUMAN Seems to function as an adapter protein. In adherens junctions may function to couple syndecans to cytoskeletal proteins or signaling components. Seems to couple transcription factor SOX4 to the IL-5 receptor (IL5RA). May also play a role in vesicular trafficking. Seems to be required for the targeting of TGFA to the cell surface in the early secretory pathway.[1] [2] [3] Publication Abstract from PubMedThe 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. Discovery of a PDZ Domain Inhibitor Targeting the Syndecan/Syntenin Protein-Protein Interaction: A Semi-Automated "Hit Identification-to-Optimization" Approach.,Hoffer L, Garcia M, Leblanc R, Feracci M, Betzi S, Ben Yaala K, Daulat AM, Zimmermann P, Roche P, Barral K, Morelli X J Med Chem. 2023 Apr 13;66(7):4633-4658. doi: 10.1021/acs.jmedchem.2c01569. Epub , 2023 Mar 20. PMID:36939673[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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