Molecular Dynamics and Solvated Interaction Energy Prioritize Cannabidiol and Cannabinol as Variant-Spanning...

Area of Science:

• Virology
• Computational Chemistry
• Pharmacology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes its spike receptor-binding domain (RBD) to engage angiotensin-converting enzyme 2 (ACE2) for host cell entry.
• Cannabinoid compounds have emerged as potential inhibitors of viral entry by binding to the spike protein and modulating host responses.

Purpose of the Study:

• To computationally identify and prioritize cannabis-derived compounds that can act as interfacial blockers of the SARS-CoV-2 RBD-ACE2 complex across different viral variants.
• To evaluate the binding stability and energetic contributions of selected phytocannabinoids to the RBD-ACE2 interface.

Main Methods:

• An integrated computational pipeline involving molecular docking and extensive all-atom molecular dynamics (MD) simulations (200 ns) was employed.
• Binding free energies were calculated using molecular mechanics/generalized Born surface area (MM/GBSA) and solvated interaction energy (SIE).
• Analysis of per-residue contributions, solvent-accessible surface area (SASA), and residue interaction networks elucidated binding mechanisms.

Main Results:

• Eleven phytocannabinoids were docked, with preferential binding observed in pocket 1 of the RBD-ACE2 interface.
• Cannabidiol (CBD) and cannabinol (CBN) were the only compounds that maintained stable binding across wild-type, Delta, and Omicron BA.1 variants.
• CBN exhibited superior binding in the wild-type, while CBD showed preserved binding in Omicron BA.1, driven by electrostatic complementarity and solvation effects rather than surface coverage.
• Both CBD and CBN were shown to weaken the RBD-ACE2 interaction by perturbing key residues in both the RBD and ACE2.

Conclusions:

• CBD and CBN are identified as effective, variant-spanning interface disruptors of the SARS-CoV-2 RBD-ACE2 interaction.
• The study demonstrates the utility of MD-based free-energy calculations in discovering drugs targeting dynamic viral protein-protein interfaces.
• These findings support the development of cannabinoid-based therapeutics for combating SARS-CoV-2 and potentially other evolving viral threats.