Rapid Structure-Based Screening Informs Potential Agents for Coronavirus Disease (COVID-19) Outbreak*

Abstract

Coronavirus Disease 2019 (COVID-19), caused by the novel coronavirus, has spread rapidly across China. Consequently, there is an urgent need to sort and develop novel agents for the prevention and treatment of viral infections. A rapid structure-based virtual screening is used for the evaluation of current commercial drugs, with structures of human angiotensin converting enzyme II (ACE2), and viral main protease, spike, envelope, membrane and nucleocapsid proteins. Our results reveal that the reported drugs Arbidol, Chloroquine and Remdesivir may hinder the entry and release of virions through the bindings with ACE2, spike and envelope proteins. Due to the similar binding patterns, NHC (β-d-N4-hydroxycytidine) and Triazavirin are also in prospects for clinical use. Main protease (3CLpro) is likely to be a feasible target of drug design. The screening results to target 3CL-pro reveal that Mitoguazone, Metformin, Biguanide Hydrochloride, Gallic acid, Caffeic acid, Sulfaguanidine and Acetylcysteine seem be possible inhibitors and have potential application in the clinical therapy of COVID-19.

Computational Simulation of HIV Protease Inhibitors to the Main Protease (Mpro) of SARS-CoV-2: Implications for COVID-19 Drugs Design

“…The crystal structure of SARS-CoV-2 Mpro in complex with ligand N3 (PDB: 6LU7) was retrieved from the RCSB PDB database and used in the docking process [ 24 ]. The binding site was assigned according to the location of ligand N3, and the redocked pose of N3 with SARS-CoV-2 Mpro was in a manner consistent with the crystallographic pose (PDB: 6LU7), with the RMSD (root-mean-square deviation) value being less than 0.200 nm.…”

“…All the hetero-atoms of the nonprotein part were suppressed. At physiological pH, missing hydrogen atoms were added based on the expected charge distributions of amino acids [ 24 ]. Then, the charmm27 force field was used in the Generalized Born with a simple Switching (GBSW) solvent model.…”

“…The entropic contribution (T Δ S) is evaluated with the normal-mode method [ 45 , 46 ]. The dielectric constants of the solvent and solute are 80 and 1, respectively [ 24 , 50 ]. Each residue contribution for the binding affinity was also decomposed by the MM–GBSA method.…”

Triazavirin—A Novel Effective Antiviral Drug

“…The clinical efficacy of Riamilovir (Triazavirin) and the safety of the drug for treatment of patients with moderate COVID-19 were evaluated independently by several research teams in the Russian Federation (RF) [ 20 , 21 , 22 , 23 , 24 , 25 , 77 ] and The People’s Republic of China (PRC) [ 26 , 27 ].…”

“…According to virtual screening of the known antiviral drugs against SARS-CoV-2 on the basis of molecular docking data, Triazavirin is not capable of forming stable complexes with angiotensin-converting enzyme 2 (+13.77 kcal/mol), envelope protein (+11.68 kcal/mol), the spike protein (+6.05 kcal/mol), 3CL protease (+6.69 kcal/mol), membrane (+7.71 kcal/mol) and nucleocapsid proteins (+7.02 kcal/mol). Nevertheless, Yang and co-authors found the clinical use of Triazavirin to be rather promising due to a similarity of its binding pattern with that of 𝛽-d-N4-hydroxycytidine relative to ACE2, the spike protein and 3CL protease [ 77 ].…”