Discovery of a PDZ Domain Inhibitor Targeting the Syndecan/Syntenin Protein–Protein Interaction: A Semi-Automated “Hit Identification-to-Optimization” Approach - Archive ouverte HAL Access content directly
Journal Articles Journal of Medicinal Chemistry Year : 2023

Discovery of a PDZ Domain Inhibitor Targeting the Syndecan/Syntenin Protein–Protein Interaction: A Semi-Automated “Hit Identification-to-Optimization” Approach

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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Dates and versions

hal-04048842 , version 1 (28-03-2023)

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Laurent Hoffer, Manon Garcia, Raphael Leblanc, Mikael Feracci, Stéphane Betzi, et al.. Discovery of a PDZ Domain Inhibitor Targeting the Syndecan/Syntenin Protein–Protein Interaction: A Semi-Automated “Hit Identification-to-Optimization” Approach. Journal of Medicinal Chemistry, 2023, ⟨10.1021/acs.jmedchem.2c01569⟩. ⟨hal-04048842⟩
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