Receptor-Selective Modulation of Cannabinoid Signaling by Cardamonin: Integrating Molecular Dynamics, Free Energy Calculations, and Behavioral Validation
Abstract
Cardamonin, a naturally occurring chalcone derivative, has demonstrated potential as a modulator of the endocannabinoid system (ECS). However, its interactions with cannabinoid receptors CB1 and CB2 are not fully understood. This work integrates in silico and in vivo methodology to examine the structural dynamics and pharmacological effects of cardamonin. Molecular dynamics simulations spanning 1000 ns demonstrated that cardamonin shows modest, receptor-dependent effects on CB1 dynamics, as shown by diminished root-mean-square deviation (RMSD) and fluctuation (RMSF), reduced solvent-accessible surface area (SASA), and increased hydrogen bonding. Principal component analysis (PCA) further demonstrated increased conformational sampling in CB1 following ligand binding, implying alteration of receptor flexibility. Conversely, CB2 had little structural alterations, indicating weaker or less selective binding. MM/PBSA binding energy calculations corroborated these findings, revealing that cardamonin exhibited comparable binding affinity at CB1 (-19.58 ± 6.49 kcal/mol) and CB2 (-18.76 ± 3.97 kcal/mol), with only a slight numerical tendency toward CB1. Both interactions were mild relative to the native ligands. Functional validation using Von Frey and Hargreaves behavioral experiments indicated that cardamonin markedly reduced mechanical and thermal hypersensitivity in mouse models. Significantly, some analgesic effects were maintained even with specific CB1 or CB2 blockade,…
Read the paper
Related studies
- eggNOG 5.0: a hierarchical, functionally and phylogenetically annotated orthology resource based on 5090 organisms and 2502 viruses
- Online Survival Analysis Software to Assess the Prognostic Value of Biomarkers Using Transcriptomic Data in Non-Small-Cell Lung Cancer
- OptiType: precision HLA typing from next-generation sequencing data
- Nicotinic Cholinergic System and COVID-19: In Silico Identification of an Interaction between SARS-CoV-2 and Nicotinic Receptors with Potential Therapeutic Targeting Implications
- Saccharomyces cerevisiae cells have three Omega class glutathione S-transferases acting as 1-Cys thiol transferases
- Hemolysis at low blood flow rates: in-vitro and in-silico evaluation of a centrifugal blood pump
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.