Abstract
The SARS-CoV-2 main protease (Mpro) is an attractive target towards discovery of drugs to treat COVID-19 because of its key role in virus replication. The atomic structure of Mpro in complex with an α-ketoamide inhibitor (Lig13b) is available (PDB ID:6Y2G). Using 6Y2G and the prior knowledge that protease inhibitors could eradicate COVID-19, we designed a computational study aimed at identifying FDA-approved drugs that could interact with Mpro. We searched the DrugBank and PubChem for analogs and built a virtual library containing ∼33,000 conformers. Using high-throughput virtual screening and ligand docking, we identified Isavuconazonium, a ketoamide inhibitor (α-KI) and Pentagastrin as the top three molecules (Lig13b as the benchmark) based on docking energy. The ΔGbind of Lig13b, Isavuconazonium, α-KI, Pentagastrin was −28.1, −45.7, −44.7, −34.8 kcal/mol, respectively. Molecular dynamics simulation revealed that these ligands are stable within the Mpro active site. Binding of these ligands is driven by a variety of non-bonded interaction, including polar bonds, H-bonds, van der Waals and salt bridges. The overall conformational dynamics of the complexed-Mpro was slightly altered relative to apo-Mpro. This study demonstrates that three distinct classes molecules, Isavuconazonium (triazole), α-KI (ketoamide) and Pentagastrin (peptide) could serve as potential drugs to treat patients with COVID-19.
Highlights
With over 4.53 million infections and 307108 deaths today (15th May 2020), the world is witnessing a calamitous viral pandemic caused by a new strain of a coronavirus, scientifically referred to as SARS-Cov[2], the causative agent of corona virus disease (COVID-19)
This study demonstrates that three distinct classes molecules, Isavuconazonium, α-ketoamide inhibitor derivative (α-KI) and Pentagastrin could serve as potential drugs to treat patients with COVID-19
The rationale behind performing molecular docking is to make a systematic prediction of the ideal pose or conformation of a ligand in a protein’s binding site, which could be taken further for molecular dynamics simulation studies
Summary
With over 4.53 million infections and 307108 deaths today (15th May 2020), the world is witnessing a calamitous viral pandemic caused by a new strain of a coronavirus, scientifically referred to as SARS-Cov[2], the causative agent of corona virus disease (COVID-19). Even though the death rate is lower than the historical coronavirus-associated SARS, the recovery rate seems to be relatively protracted. This has resulted in straining health care systems globally and sub-Saharan Africa may become the epicentre if the infection is not controlled effectively. In most countries around the world, the only means of control is by instating a nationwide lockdown. Countries, such as South Africa, that took this initiative, disastrous it was on the economy, have witnessed a slower infection rate, from 45% to less than 4% (between 27th March 2020 and 10th of April 2020)
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