Introduction
- Inhibiting Protein-Protein Interactions (PPIs) with small molecules is considered by many to be the most difficult area of drug discovery.
- Here we developed a method for designing custom templates into empty binding pockets and designed a library of small molecules to inhibit interaction human NPC1 and Zaire Ebolavirus (EBOV) GP1 protein.
(Panel A)
Method
- The NPC1 pocket of interest without template molecule (Panel B) is the input for the Sextant process for building small molecule templates. (Panel C)
- QuADD returned a library of candidates, including 470 with dGs more favorable than the Sextant template. (Panel D)
Conclusions
- The Sextant method designs templates into binding pockets.
- QuADD returns a strong candidate library (Panel E)
- This method can be applied to other protein pockets.
- This work is a part of a DARPA IMPAQT contract. More details here.
