Protein 14-3-3ζ sequesters the pro-apoptotic BAD protein—enhancing cancer survival including in many colorectal cancers—yet it remains largely unexplored as a therapeutic target. We computationally predicted and then showed in vitro and in vivo that some FDA-approved drugs induce apoptosis by inhibiting 14-3-3ζ–BAD, but recognize drug repurposing has a low chance of success; in this proposal we aim to identify and structurally optimize new chemical material for 14-3-3ζ–BAD. We integrate structure and ligand-based pharmacophore modeling, ultra-high throughput virtual screening, molecular docking, MD simulations, and free energy perturbation calculations with our synthetic chemistry and in vitro assays for ligand discovery. We want to incorporate BioSolveIT tools such as infiniSee xREAL and expand our screen to 2.4 trillion compounds. This will be the first detailed CADD study aimed at disrupting the 14-3-3ζ–BAD complex.
Samra intends to achieve the following milestones:
- Protein Preparation, structure and ligand-based pharmacophore modeling: virtual screening workflow (VSW) with infiniSee xREAL and Quickshape
- Docking (SP/XP and IFD), first phase of molecular dynamics (MD) simulations; analyses and optimization
- Second phase of MD simulations, free energy perturbation (FEP), in vitro testing of identified hit compounds and optimization