Integrated Discovery Platform Characterizes Novel NLRX1 Ligands

BLACKSBURG, VA: Dec. 29, 2015 – Nucleotide-binding domain and leucine-rich repeat containing (NLR) family are intracellular sentinels of cytosolic homeostasis that orchestrate immune and inflammatory responses in infectious and immune-mediated diseases. NLRX1 is a mitochondrial-associated NOD-like receptor involved in the modulation of immune and metabolic processes. Understanding the mechanisms of by which NLRX1 protects from gut inflammation has the potential to accelerate the development of safer and more effective treatments for inflammatory bowel disease (IBD), a widespread and debilitating disease that affect over 4 million people worldwide.

Researchers at Virginia Tech’s Nutritional Immunology and Molecular Medicine Laboratory (www.nimml.org) recently released a study in the open-access journal PLOS ONE utilizing molecular docking approaches to investigate the structure of NLRX1 and experimentally assessing binding to naturally occurring compounds from several natural product and lipid databases.

Screening of compound libraries predicts targeting of NLRX1 by conjugated trienes, polyketides, prenol lipids, sterol lipids, and coenzyme A-containing fatty acids for activating the NLRX1 pathway. The ligands of NLRX1 were identified by docking punicic acid, the dominant component of pomegrante seed oil, and docosahexaenoic acid, another anti-inflammatory fatty acid found in fish oil, to human NLRX1. Their binding and that of positive control RNA to NLRX1 were experimentally determined by advanced biochemical methods.

“Our study employed NIMML’s integrated drug discovery pipeline consisting of molecular docking approaches followed by biochemical,in vitro and in vivo validation in mice with colitis. Our results indicate that NLRX1 acts as a cytosolic sensor of lipids that operates in the interface of immunity and metabolism. Additionally, these approaches identified and validated experimentally the binding site of these lipid molecules to NLRX1”, said Pinyi Lu, a research assistant of NIMML, Further research at NIMML is using smart simulations to test NLRX1-based therapies in a large cohort of synthetic Crohn’s disease patients.

“Integrating modeling into the nutritional immunology research cycle will help accelerate the knowledge discovery process. Similar to our previous research on lanthionine synthetase C-like 2, this study has used NLRX1 as an example to demonstrate that combining computational modeling with experimental validation provides an efficient path to both fundamental mechanistic discovery as well as product development.”, said Josep Bassaganya-Riera, Professor and Director of the NIMML at Virginia Tech.