Potential SARS-CoV-2 protease M^pro inhibitors: repurposing FDA-approved drugs

Abstract

Using as a template the crystal structure of the SARS-CoV-2 main protease, we developed a pharmacophore model of functional centers of the protease inhibitor-binding pocket. With this model, we conducted data mining of the conformational database of FDA-approved drugs. This search brought 64 compounds that can be potential inhibitors of the SARS-CoV-2 protease. The conformations of these compounds undergone 3D fingerprint similarity clusterization. Then we conducted docking of possible conformers of these drugs to the binding pocket of the protease. We also conducted the same docking of random compounds. Free energies of the docking interaction for the selected compounds were clearly lower than random compounds. Three of the selected compounds were carfilzomib, cyclosporine A, and azithromycin—the drugs that already are tested for COVID-19 treatment. Among the selected compounds are two HIV protease inhibitors and two hepatitis C protease inhibitors. We recommend testing of the selected compounds for treatment of COVID-19.

Haste makes waste: A critical review of docking‐based virtual screening in drug repurposing for SARS‐CoV‐2 main protease (M‐pro) inhibition

“…128,129 In addition to docking, other computational methods have been used to identify new SARS-CoV-2 M-pro inhibitors. These methods include pharmacophores 76,130,131 ; combined quantum mechanics/molecular mechanics (QM/MM) methods 132,133 ; a Docking Consensus Approach and Common Hits Approach that combine molecular dynamics simulations with molecular docking and pharmacophores, respectively 131 ; interactive molecular dynamics simulation in virtual reality 134 ; Quantitative Structure-activity Relationship models, 115 and binding free energies calculations. 82,116,135 Among the various methods to calculate protein-ligand binding affinities, Free Energy Perturbation (FEP) has been used successfully to predict new M-pro inhibitors.…”

Targeting the Spike: Repurposing Mithramycin and Dihydroergotamine to Block SARS-CoV-2 Infection

“…This includes Wilms tumor, rhabdomyosarcoma, Ewing’s sarcoma, trophoblastic neoplasm, testicular cancer, and certain types of ovarian cancer . mithramycin and dihydroergotamine have been also computationally studied by other groups in the search of antivirals against SARS-CoV-2, ,, but none of them has been tested in vitro or in vivo. ,, Mithramycin is an antibiotic that inhibits the synthesis of the bacterial RNA () and is not currently on the market because it is not approved for cancer therapy. Dihydroergotamine is a widely used antimigraine drug approved in 1946, still on the market also as a nasal spray formulation (ideal for the intended use against respiratory disease) with well-known record of dosage and side effects on patients.…”

“…36 mithramycin and dihydroergotamine have been also computationally studied by other groups in the search of antivirals against SARS-CoV-2, 18,24,25 but none of them has been tested in vitro or in vivo. 19,25,26 Mithramycin is an antibiotic that inhibits the synthesis of the bacterial RNA (https://www. fermentek.com/product/mithramycin-plicamycin) and is not currently on the market because it is not approved for cancer therapy.…”

A Study of Drug Repurposing to Identify SARS-CoV-2 Main Protease (3CLpro) Inhibitors

“…Cynarine, eravacycline, and prexasertib represented outstanding inhibitory activity with IC 50 values of 1.82 μ M, 1.65 μM, and 1.99 μM, respectively. Interestingly, eravacycline was also identified in recent virtual screens of FDA-approved drugs for repurposing as COVID-19 treatments [ 14 , 15 ]. The docking modes of cynarine, eravacycline, and prexasertib indicated that between the two catalytic dyad residues His41 and Cys145, Cys145 was involved in binding with all three chemicals ( Figure 4 ).…”