Natural Products: Untapped Potential Against Inflammation
The Challenge: Mining Plant-Origin Natural Products for TNF/RANKL Inhibition
Despite the success of anti-TNF biologics, there's a need for orally available, cost-effective alternatives. Plant-origin natural products offer a vast, largely unexplored chemical space. The challenge was to develop an efficient computational pipeline to screen this natural product space and identify compounds that can directly inhibit TNF and its close relative RANKL — key mediators of chronic inflammatory conditions including rheumatoid arthritis and osteoporosis.
Our Approach
An integrated drug discovery pipeline from natural product databases to validated hits
Natural Product Database Screening
Developed an in silico drug discovery pipeline specifically designed for virtual screening of plant-origin natural products. Curated comprehensive databases of NP compounds with potential for direct TNF and RANKL inhibition at the trimerization interface.
Structure-Based Virtual Screening & Docking
Performed molecular docking of natural products against the TNF and RANKL crystal structures. Prioritized 15 compounds from the virtual screening as potential direct TNF inhibitors for experimental testing.
Compound Acquisition & Testing
Obtained 15 prioritized NP candidates and subjected them to comprehensive in vitro biological evaluation. Tested compounds for direct TNF function inhibition and RANKL blocking activity.
Molecular Dynamics Simulations
Extended MD simulations using the fully automated EnalosMD suite rationalized the mode of action at the molecular level, confirming stable binding at the trimerization interfaces and explaining structure-activity relationships.
In Vitro Validation
Identified two potent direct TNF inhibitors with low micromolar IC50 values and minimal toxicity even at high concentrations. Both compounds showed dose-dependent inhibition of TNF function.
Dual Inhibitor Discovery — Compound A11
Most significantly, compound A11 (Ampelopsin H) proved to be a dual inhibitor of both TNF and RANKL — the first natural product small-molecule dual inhibitor ever reported. This represents a breakthrough in NP-based drug discovery for inflammatory diseases.