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.
Key Results
Powered by NovaMechanics Software
Enalos Asclepios KNIME Nodes
Used for molecular dynamics simulations and structure-based virtual screening. The EnalosMD suite provided fully automated MD workflows for validating natural product binding modes and rationalizing structure-activity relationships.
Learn moreIsalos Analytics Platform
Enabled comprehensive compound analysis, molecular descriptor calculations, and structure-activity relationship visualization. Supported the chemical data management and analysis workflow for natural product screening.
Learn moreRelated Publication
In Silico Discovery of Plant-Origin Natural Product Inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NF-κB Ligand (RANKL)
This study established NovaMechanics' capability to mine the vast chemical space of plant-origin natural products for therapeutic hits. The discovery of compound A11 (Ampelopsin H) — the first natural product dual TNF/RANKL inhibitor — opens new avenues for developing affordable, plant-derived treatments for inflammatory diseases including rheumatoid arthritis and osteoporosis. The EnalosMD pipeline demonstrated here became the foundation for the Enalos Asclepios KNIME nodes used in subsequent studies.
Have a Similar Challenge?
Let's explore how our computational drug discovery pipeline can accelerate your research into natural products.
Get in Touch