Nutraceuticals Targeting Cannabinoid Receptor 1 and Transient Receptor Potential Vanilloid 1 for Pain Relief: A...

This study examined the binding affinities and therapeutic potential of natural products targeting pain-related receptors using molecular docking and molecular dynamics (MD) simulations. Drug-like properties and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses were also conducted.

AutoDock Vina (The Scripps Research Institute, La Jolla, CA, USA) was used for docking against pain-related receptors, including transient receptor potential vanilloid 1 (TRPV1), cyclooxygenase-2 (COX-2), cannabinoid receptor 1 (CB1), mu-opioid receptor, and nicotinic acetylcholine receptors. Celecoxib was included as a reference drug for docking score comparison. Protein-ligand complex stability was assessed via 100-nanosecond (ns) MD simulations using GROMACS (GROningen MAchine for Chemical Simulations; the University of Groningen, Netherlands), analyzing root mean square deviation (RMSD) and radius of gyration (Rg). Drug-likeness was evaluated by Lipinski's rule of five, and ADMET analysis was performed for pharmacokinetics and toxicity profiling.

Ginsenoside Rb1 exhibited a strong affinity for TRPV1 (-9.5 kcal/mol) and mu-opioid (-9.0 kcal/mol) receptors, suggesting its potential as a non-opioid analgesic candidate. Cyanidin 3-O-rutinoside demonstrated high binding to TRPV1 (-9.35 kcal/mol), COX-2 (-9.65 kcal/mol), and CB1 (-9.18 kcal/mol), surpassing the reference drug celecoxib (-7.22 kcal/mol) in COX-2 binding. MD simulations confirmed complex stability, with RMSD (~3.0 Å) and Rg (~3.0 nm) values lower than unbound proteins. Most compounds met Lipinski's criteria, indicating good oral bioavailability. ADMET analysis revealed favorable absorption and distribution with low toxicity.

Ginsenoside Rb1 and cyanidin 3-O-rutinoside exhibit high binding affinity, stability, and favorable pharmacokinetic properties, supporting their potential as non-opioid analgesic candidates. Their ability to modulate pain pathways in vitro and in vivo warrants further investigation.