Identification of cannabichromevarin as a potent stabilizer of the measles virus prefusion F protein: structural insights from long-timescale molecular dynamics

Measles virus (MeV) remains a serious public health concern, necessitating the development of effective antivirals targeting the viral fusion (F) glycoprotein. This study employed a robust computational pipeline, including molecular docking, 1000 ns all-atom molecular dynamics (MD) simulations, and free energy landscape (FEL) analysis, to evaluate minor cannabinoids as novel inhibitors of the MeV F protein. Initial virtual screening identified Cannabichromenic acid (CBCA), Cannabichromevarin (CBCV), and Cannabiripsol (CBR) as high-affinity leads, with docking scores of − 8.5, − 8.2, and − 8.1 kcal/mol, respectively, outperforming the reference inhibitor AS-48 (− 7.6 kcal/mol). Post-MD binding free energy calculations (MM-GBSA) further confirmed the thermodynamic superiority of CBCV (ΔG_bind = − 44.7 kcal/mol) and CBCA (ΔG_bind = − 30.1 kcal/mol) over the reference. Dynamic analyses revealed that CBCV and CBCA effectively stabilize the F protein in its inactive prefusion conformation through a conformational locking mechanism. CBCV induced the most significant structural compaction (Rg = 2.4 nm) and displayed the sharpest global energy minimum (0.3 kcal/mol) in the FEL. Furthermore, ADMET profiling and ProTox-3.0 toxicity modeling identified CBCV as the most promising lead, possessing excellent drug-likeness, an inactive toxicity profile, and predicted blood-brain barrier permeability. This work establishes minor cannabinoids as novel scaffolds for anti-MeV drug development, positioning CBCV as a strong candidate for treating systemic and neurological complications of measles, such as Subacute Sclerosing Panencephalitis.