Characterization of binding kinetics and intracellular signaling of new psychoactive substances targeting cannabinoid receptor using transition-based reweighting method

New psychoactive substances (NPS) targeting cannabinoid receptor 1 pose a significant threat to society as recreational abusive drugs that have pronounced physiological side effects. These greater adverse effects compared to classical cannabinoids have been linked to the higher downstream β-arrestin signaling. Thus, understanding the mechanism of differential signaling will reveal important structure-activity relationships essential for identifying and potentially regulating NPS molecules. In this study, we simulate the slow (un)binding process of NPS MDMB-Fubinaca and classical cannabinoid HU-210 from CB1 using multi-ensemble simulation to decipher the effects of ligand binding dynamics on downstream signaling. The transition-based reweighing method is used for the estimation of transition rates and underlying thermodynamics of (un)binding processes of ligands with nanomolar affinities. Our analyses reveal major interaction differences with transmembrane TM7 between NPS and classical c..., , , # Characterization of binding kinetics and intracellular signaling of new psychoactive substances targeting cannabinoid receptor using transition-based reweighting method [https://doi.org/10.5061/dryad.4f4qrfjq5](https://doi.org/10.5061/dryad.4f4qrfjq5) ## Description of the data and file structure This README file was generated on 2025-03-02 by Soumajit Dutta #### Contributors * Soumajit Dutta : Chemical and Biomolecular Engineering, University of Illinois Urbana-Champaign * Diwakar Shukla (Corresponding Author) : Chemical and Biomolecular Engineering, University of Illinois Urbana-Champaign #### Overview The dataset contains molecular dynamics (MD) trajectories obtained using various simulation techniques for the associated research paper, along with the files containing corresponding parameter and topology. All simulations employed the CHARMM36m force field for proteins, while synthetic cannabinoids were parameterized using the CGenFF force field. Well-Tempered Metadynamics si...,