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Discovery of a PDZ Domain Inhibitor Targeting the Syndecan/Syntenin Protein-Protein Interaction: A Semi-Automated "Hit Identification-to-Optimization" Approach. | LitMetric

AI Article Synopsis

  • The DOTS strategy integrates molecular dynamic simulations, computer-aided design, and automated evaluation to enhance drug discovery by efficiently identifying and optimizing potential drug candidates.
  • This approach was successfully tested on the syntenin protein, leading to the development of a highly effective small molecule inhibitor specifically targeting its second PDZ domain.
  • The key to DOTS' effectiveness lies in its consideration of protein conformations and the synthetic feasibility of compounds during the optimization phase, making it applicable to various protein targets with known structures.

Article 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.

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Source
http://dx.doi.org/10.1021/acs.jmedchem.2c01569DOI Listing

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