Research: Insilico Rational Design of N-Acetylgalactosamine Modification to Deliver Short Interfering RNA (siRNA) Therapeutic
Mentors: Dr. Maio and Dr. Chen
Research Location: Regeneron
Abstract:
N-Acetylgalactosamine (delivery name: GalNac) is an amino sugar derivative of galactose that helps cells communicate with one another. It has been shown to be involved in improving joint stiffness and pain, stomach and intestine barrier protection, and sun-induced skin dark spots. Olix Pharmaceuticals recently acquired a patent for the GalNac delivery platform, which will be used to treat a variety of liver ailments, including liver fibrosis. Rather than targeting the DNA itself, antisense oligonucleotide therapies target the RNA created from DNA, which provides the information directing protein synthesis. More interactions from a specific portion of GalNac would have an influence due to reduced off-target effects and improved activity in the drug's bigger therapeutic window. A simulation program called Pymol allowed us to replicate the different structures and analyze the data. The five different structures replicated include: Benzoyl, Ethyl, Cyclohexene, Trifluoromethyl, and Propyl. Data was analyzed and the absolute energy and library dock was determined using another program called Biovia. For the results, the lower the absolute energy means that less energy is required to bind. Our results concluded that lead compounds, Ethyl and Trifluoromethyl, had similar absolute energy and high library doc scores. Ethyl had an absolute energy of 15.58 J, the same as the original GalNAc structure, and a library dock score of 110.6, which was higher than the original GalNAc structure's library doc score. This means that they both improve the acetyl group function so that the drug can be delivered faster and more efficiently. This research will lead to future developments needed to synthesize Ethyl and/or Trifluoromethyl as a real ligand in the lab.