Molecular Modeling Targeting the ACE2 Receptor with Cannabis sativa's Active Ingredients for Antiviral Drug Discovery against SARS-CoV-2 Infections

Abstract

The emergence of a novel coronavirus that later on rendered a global pandemic, caused desperation within the communities and drove increased interest in exploring medicinal plant-based therapeutics to treat and prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infections. Many medicinal plants have been reported to have antiviral, anti-inflammatory, and immunomodulatory effects that hinder, cure, or ease the symptoms of COVID-19 infection. This exploratory study seeks to dock the active components of Cannabis sativa, a natural plant with several pharmacological and biological properties, with the angiotensin-converting enzyme II (ACE2) receptor. A total of 3 C. sativa active components have been found to bind to the ACE2 protein active site and could inhibit spike binding, although they do not compete directly with the receptor-binding domain (RBD) of SARS-CoV-2. 6-Prenylapigenin, cannabivarin (CBN-C3), and Δ8-tetrahydrocannabinolic acid-A (Δ8-THCA) have a greater affinity (-8.3, -8.3, and -8.0 kcal/mol, respectively) and satisfactory interaction with ACE2 than its inhibitor MLN-4760 (-7.1 kcal/mol). These potential drugs with higher affinity for the ACE2 receptor and adequate absorption, distribution, metabolism, excretion, and toxicity (ADMET) values are candidates for treating or preventing SARS-CoV-2 infections. In vitro and in vivo investigations are needed to evaluate further the efficacy and toxicity of these hit compounds.

Keywords: ACE2; ADMET; COVID-19; Cannabis sativa; Medicinal plant; SARS-CoV-2; drug discovery; molecular docking; spike.

Figure 1.

3D and 2D structures of potential ligands derived from Cannabis sativa and MLN-4760 inhibitor of ACE2. All bond distances are from 2.2 to 2.4 Å. Top left: MLN-4760, top right: 6-prenylapigenin, down left: CBN-C3, and down right: Δ8-THCA. Δ8-THCA indicates Δ8-tetrahydrocannabinolic acid-A; CBN-C3, cannabivarin.

Figure 2.

The bioavailability radars and BOILED-Egg for reference and hit compounds (A) MLN-4760 (reference), (B) 6-prenylapigenin, (C) Δ8-THCA, and (D) CBN-C3.