Potential Role of Colchicine in Combating COVID-19 Cytokine Storm and Its Ability to Inhibit Protease Enzyme of SARS-CoV-2 as Conferred by Molecular Docking Analysis

Abstract

Despite the advance in the management of Coronavirus disease 2019 (COVID-19), the global pandemic is still ongoing with a massive health crisis. COVID-19 manifestations may range from mild symptoms to severe life threatening ones. The hallmark of the disease severity is related to the overproduction of pro-inflammatory cytokines manifested as a cytokine storm. Based on its anti-inflammatory activity through interfering with several pro and anti-inflammatory pathways, colchicine had been proposed to reduce the cytokine storm and subsequently improve clinical outcomes. Molecular docking analysis of colchicine against RNA-dependent RNA polymerase (RdRp) and protease enzymes of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) revealed that colchicine provided a grid-based molecular docking method, C-DOCKER interaction energy 64.26 and 47.53 (Kcal/mol) with protease and RdRp, respectively. This finding indicated higher binding stability for colchicine-protease complexes than the colchicine-RdRp complex with the involvement of seven hydrogen bonds, six hydrogen acceptors with Asn142, Gly143, Ser144, and Glu166 and one hydrogen-bond donors with Cys145 of the protease enzyme. This is in addition to three hydrophobic interactions with His172, Glu166, and Arg188. A good alignment with the reference compound, Boceprevir, indicated high probability of binding to the protease enzyme of SARS-CoV-2. In conclusion, colchicine can ameliorate the destructive effect of the COVID-19 cytokine storm with a strong evidence of antiviral activity by inhibiting the protease enzyme of SARS-CoV-2.

Keywords: COVID-19; RNA polymerase; SARS-CoV-2; colchicine; cytokine storm; molecular docking; protease inhibitor.

Figure 1

Mechanism of the anti-inflammatory activity of colchicine during infection with SARS-CoV-2. NLRP3 inflammasome (NOD-like receptor (NLR) subfamily pyrin domain containing 3 inflammasome); IL, Interleukin, TNF, Tumor necrosis factor.

Figure 2

Interaction of Colchicine (blue) with the key amino acids of the protease enzyme of SARS-CoV-2, hydrogen bond (green) hydrophobic (grey).

Figure 3

Interaction of Colchicine (blue) with the key amino acids of the polymerase (RdRp) enzyme of SARS-CoV-2, hydrogen bond (green) hydrophobic (orange).

Figure 4

Alignment of Colchicine (blue) with Boceprevir (protease inhibitor) (purple) in the protease active site of SARS-CoV-2.