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

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.