Potential COVID-19 Protease Inhibitors: Repurposing FDAapproved Drugs

10.26434/chemrxiv.12093900 ◽

2020 ◽

Author(s):

Valentina Kouznetsova ◽

David Huang ◽

Igor F. Tsigelny

Keyword(s):

Protease Inhibitors ◽

Binding Pocket ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Free Energies ◽

Inhibitor Binding ◽

Approved Drugs ◽

Docking Interaction ◽

Potential Inhibitors ◽

Fda Approved Drugs

Using as a template the crystal structure of COVID-19 protease, we developed a pharmacophore of functional centers of the protease inhibitor-binding pocket. Then we conducted data mining of the conformational database of FDA-approved drugs. This search brought 64 compounds that can be potential inhibitors of COVID-19 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 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.<br><br>

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Potential COVID-19 papain-like protease PLpro inhibitors: repurposing FDA-approved drugs

PeerJ ◽

10.7717/peerj.9965 ◽

2020 ◽

Vol 8 ◽

pp. e9965 ◽

Cited By ~ 1

Author(s):

Valentina L. Kouznetsova ◽

Aidan Zhang ◽

Mahidhar Tatineni ◽

Mark A. Miller ◽

Igor F. Tsigelny

Keyword(s):

Crystal Structure ◽

Pharmacophore Model ◽

Binding Pocket ◽

Free Energies ◽

Inhibitor Binding ◽

Drug List ◽

Approved Drugs ◽

Docking Interaction ◽

Potential Inhibitors ◽

Fda Approved Drugs

Using the crystal structure of SARS-CoV-2 papain-like protease (PLpro) as a template, we developed a pharmacophore model of functional centers of the PLpro inhibitor-binding pocket. With this model, we conducted data mining of the conformational database of FDA-approved drugs. This search identified 147 compounds that can be potential inhibitors of SARS-CoV-2 PLpro. The conformations of these compounds underwent 3D fingerprint similarity clusterization, followed by docking of possible conformers to the binding pocket of PLpro. Docking of random compounds to the binding pocket of protease was also done for comparison. Free energies of the docking interaction for the selected compounds were lower than for random compounds. The drug list obtained includes inhibitors of HIV, hepatitis C, and cytomegalovirus (CMV), as well as a set of drugs that have demonstrated some activity in MERS, SARS-CoV, and SARS-CoV-2 therapy. We recommend testing of the selected compounds for treatment of COVID-19

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HIV protease inhibitors saquinavir and nelfinavir are potent inhibitors of cathepsin L activity: A potential treatment for COVID-19 patients

10.21203/rs.3.rs-37258/v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Marcelo Freitas Montenegro ◽

Yousef Al-Abed ◽

Mingzhu He ◽

Kevin J. Tracey ◽

Timothy R. Billiar

Keyword(s):

Clinical Trials ◽

Cathepsin L ◽

Inhibitory Effect ◽

Host Cells ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Potential Treatment ◽

Approved Drugs ◽

Fda Approved Drugs

Abstract The 2019 coronavirus disease pandemic (COVID-19) has mobilized efforts worldwide, and several ongoing clinical trials aimed at developing a drug-based treatment for its control. Cathepsin L is an endosomal cysteine protease that mediates the cleavage of the S1 subunit of the coronavirus surface spike glycoprotein. This cleavage is necessary for coronavirus entry into human host cells and viruses/host cell endosome membrane fusion. Therefore, cathepsin L is a potential target for the treatment of COVID-19 patients. In this report, we describe a previously unknown inhibitory effect of two FDA-approved drugs, saquinavir and nelfinavir, on human cathepsin L activity. Whether the pivotal role for cathepsin L in Sars-Cov-2 infection described in vitro can be translated to humans, our results support immediate clinical trials of saquinavir or nelfinavir as a potential treatment for COVID-19 patients.

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Structural insights of human N-acetyltransferase 10 and identification of its potential novel inhibitors

Scientific Reports ◽

10.1038/s41598-021-84908-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mahmood Hassan Dalhat ◽

Hisham N. Altayb ◽

Mohammad Imran Khan ◽

Hani Choudhry

Keyword(s):

Structural Information ◽

Rna Stability ◽

Binding Pocket ◽

The Novel ◽

Amino Acid Residues ◽

Acetyl Coa ◽

Promising Therapeutic Target ◽

Approved Drugs ◽

Potential Inhibitors ◽

Fda Approved Drugs

AbstractN-acetyltransferase 10 (NAT10), is an acetyltransferase that regulates RNA stability and translation processes. Association of NAT10 with several diseases including cancer, makes it a promising therapeutic target. Remodelin is the only known NAT10 inhibitor, but the structural information related to its binding with NAT10 is still obscure. Here, we predicted the human NAT10 structure using homology modeling that was not available previously and used human NAT10 to identify the novel binding site(s) of Remodelin. The alignment of the modeled human NAT10 showed 24% identity and 37% positivity with crystal structure of tRNA (Met) cytidine acetyltransferase. Molecular docking showed binding of Remodelin with NAT10 in acetyl-CoA binding pocket. Additionally, we screened a library of FDA-approved drugs for the identification of novel inhibitors of NAT10 activity. Binding score showed that four drugs namely, Fosaprepitant (− 11.709), Leucal (− 10.46), Fludarabine (− 10.347) and Dantrolene (− 9.875) bind to NAT10 and have better binding capability when compared with Acetyl-CoA (− 5.691) and Remodelin (− 5.3). Acetyl-CoA, Remodelin, and others exhibit hits for hydrophobic, hydrophilic and hydrogen interactions. Interestingly, Remodelin and others interact with the amino acid residues ILE629, GLY639, GLY641, LEU719, and PHE722 in the Acetyl-CoA binding pocket of NAT10 similar to Acetyl-CoA. Our findings revealed that Fosaprepitant, Leucal, Fludarabine, and Dantrolene are promising molecules that can be tested and developed as potential inhibitors of NAT10 acetyltransferase activity.

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