PCSK9 Molecular Dynamics

What will molecular dynamics reveal about the drugability of PCSK9 with small molecules?

Currently, Amy is studying the dynamics of the protein-protein interaction between proprotein convertase subtilisin-like/kenexin type 9 (PCSK9) and low-density lipoprotein receptor (LDLR). The PCSK9/LDLR interaction results in decreased cellular intake and increased plasma level of LDL cholesterol, which is associated with severe cardiovascular diseases such as hypercholesterolemia. The only FDA approved drugs on the market that target this interaction are therapeutic monoclonal antibodies, which are quite costly to consumers. A small molecule alternative could reduce the cost of treatment, making it more available to those who need it worldwide. Specific targeting of protein-protein interactions with small molecules is often difficult, due to the size and chemical characteristics of the interaction site. With a novel focus on the dynamics of protein-protein interactions, there is potential to identify a way to manipulate them with small molecules.

The figure on the left is a model of different structures of PCSK9 that were generated from molecular dynamics simulation. Some of the regions of interest include those that have been experimentally shown to bind to the prodomain (red) and an LDLR peptide (blue).

This work is in collaboration with Dr. Salim Shah at Hingez Therapeutics.