Potential COVID-19 papain-like protease PLpro inhibitors: repurposing 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.

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.

Repositioning of Etravirine as a Potential CK1ε Inhibitor by Virtual Screening

Pharmaceuticals ◽

10.3390/ph15010008 ◽

2021 ◽

Vol 15 (1) ◽

pp. 8

Author(s):

Luis Córdova-Bahena ◽

Axel A. Sánchez-Álvarez ◽

Angel J. Ruiz-Moreno ◽

Marco A. Velasco-Velázquez

Keyword(s):

Molecular Dynamics ◽

Virtual Screening ◽

Noncovalent Interactions ◽

Antineoplastic Agent ◽

Pharmacophore Model ◽

Hiv Infections ◽

Binding Behavior ◽

Approved Drugs ◽

Potential Inhibitors ◽

Fda Approved Drugs

CK1ε is a key regulator of WNT/β-catenin and other pathways that are linked to tumor progression; thus, CK1ε is considered a target for the development of antineoplastic therapies. In this study, we performed a virtual screening to search for potential CK1ε inhibitors. First, we characterized the dynamic noncovalent interactions profiles for a set of reported CK1ε inhibitors to generate a pharmacophore model, which was used to identify new potential inhibitors among FDA-approved drugs. We found that etravirine and abacavir, two drugs that are approved for HIV infections, can be repurposed as CK1ε inhibitors. The interaction of these drugs with CK1ε was further examined by molecular docking and molecular dynamics. Etravirine and abacavir formed stable complexes with the target, emulating the binding behavior of known inhibitors. However, only etravirine showed high theoretical binding affinity to CK1ε. Our findings provide a new pharmacophore for targeting CK1ε and implicate etravirine as a CK1ε inhibitor and antineoplastic agent.

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.

Identification of potential inhibitors of SARS-COV-2 endoribonuclease (EndoU) from FDA approved drugs: a drug repurposing approach to find therapeutics for COVID-19

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2020.1775127 ◽

2020 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Anshuman Chandra ◽

Vaishali Gurjar ◽

Imteyaz Qamar ◽

Nagendra Singh

Keyword(s):

Drug Repurposing ◽

Approved Drugs ◽

Potential Inhibitors ◽

Fda Approved Drugs

Crystal structure of the human NK1 tachykinin receptor

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1812717115 ◽

2018 ◽

Vol 115 (52) ◽

pp. 13264-13269 ◽

Cited By ~ 9

Author(s):

Jie Yin ◽

Karen Chapman ◽

Lindsay D. Clark ◽

Zhenhua Shao ◽

Dominika Borek ◽

...

Keyword(s):

Crystal Structure ◽

Substance P ◽

Binding Pocket ◽

Computational Docking ◽

Tachykinin Receptor ◽

Approved Drugs ◽

Dynamics Simulations ◽

Receptor Modulators ◽

Further Development ◽

G Protein Coupled

The NK1 tachykinin G-protein–coupled receptor (GPCR) binds substance P, the first neuropeptide to be discovered in mammals. Through activation of NK1R, substance P modulates a wide variety of physiological and disease processes including nociception, inflammation, and depression. Human NK1R (hNK1R) modulators have shown promise in clinical trials for migraine, depression, and emesis. However, the only currently approved drugs targeting hNK1R are inhibitors for chemotherapy-induced nausea and vomiting (CINV). To better understand the molecular basis of ligand recognition and selectivity, we solved the crystal structure of hNK1R bound to the inhibitor L760735, a close analog of the drug aprepitant. Our crystal structure reveals the basis for antagonist interaction in the deep and narrow orthosteric pocket of the receptor. We used our structure as a template for computational docking and molecular-dynamics simulations to dissect the energetic importance of binding pocket interactions and model the binding of aprepitant. The structure of hNK1R is a valuable tool in the further development of tachykinin receptor modulators for multiple clinical applications.

Repurposing of FDA Approved Drugs for the Identification of Potential Inhibitors of SARS-CoV-2 Main Protease

10.26434/chemrxiv.12278066 ◽

2020 ◽

Author(s):

Abhik Kumar Ray ◽

Parth Sarthi Sen Gupta ◽

Saroj Kumar Panda ◽

Satyaranjan Biswal ◽

Malay Kumar Rana

Keyword(s):

Virtual Screening ◽

Binding Energies ◽

Great Promise ◽

Main Protease ◽

Promising Target ◽

Inhibitory Potential ◽

Novel Coronavirus ◽

Approved Drugs ◽

Potential Inhibitors ◽

Fda Approved Drugs

COVID-19, responsible for several deaths, demands a cumulative effort of scientists worldwide to curb the pandemic. The main protease, responsible for the cleavage of the polyprotein and formation of replication complex in virus, is considered as a promising target for the development of potential inhibitors to treat the novel coronavirus. The effectiveness of FDA approved drugs targeting the main protease in previous SARS-COV (s) reported earlier indicates the chances of success for the repurposing of FDA drugs against SARS-COV-2. Therefore, in this study, molecular docking and virtual screening of FDA approved drugs, primarily of three categories: antiviral, antimalarial, and peptide, are carried out to investigate their inhibitory potential against the main protease. Virtual screening has identified 53 FDA drugs on the basis of their binding energies (< -7.0 kcal/mol), out of which the top two drugs Velpatasvir (-9.1 kcal/mol) and Glecaprevir (-9.0 kcal/mol) seem to have great promise. These drugs have a stronger affinity to the SARS-CoV-2 main protease than the crystal bound inhibitor α-ketoamide 13B (-6.7 kcal/mol) or Indinavir (-7.5 kcal/mol) that has been proposed in a recent study as one of the best drugs for SARS-CoV-2. The in-silico efficacies of the screened drugs could be instructive for further biochemical and structural investigation for repurposing. The molecular dynamics studies on the shortlisted drugs are underway.

Potential Inhibitors Against Papain-like Protease of Novel Coronavirus (COVID-19) from FDA Approved Drugs

10.26434/chemrxiv.11860011.v1 ◽

2020 ◽

Cited By ~ 4

Author(s):

Rimanshee Arya ◽

Amit Das ◽

Vishal Prashar ◽

Mukesh Kumar

Keyword(s):

Life Cycle ◽

Active Site ◽

Homology Model ◽

Docking Studies ◽

Rational Selection ◽

Novel Coronavirus ◽

Approved Drugs ◽

Potential Inhibitors ◽

Fda Approved Drugs ◽

Selection Of

The cases of 2019 novel coronavirus (COVID-19) infection have been continuously increasing ever since its outbreak in China last December. Currently, there are no approved drugs to treat the infection. In this scenario, there is a need to utilize the existing repertoire of FDA approved drugs to treat the disease. The rational selection of these drugs could be made by testing their ability to inhibit any COVID-19 proteins essential for viral life-cycle. We chose one such crucial viral protein, the papain-like protease (PLpro), to screen the FDA approved drugs in silico. The homology model of the protease was built based on the SARS-coronavirus PLpro structure, and the drugs were docked in S3/S4 pockets of the active site of the enzyme. In our docking studies, fifteen FDA approved drugs, including chloroquine and formoterol, bind the target enzyme with significant affinity and good geometry, suggesting their potential to be utilized against the virus.

Virtual Screening of FDA Approved Drugs Against Nsp15 Endoribonuclease from SARS CoV-2

10.26434/chemrxiv.13265519 ◽

2020 ◽

Author(s):

Althaf Shaik ◽

Nalini Natarajan ◽

Sivapriya Kirubakaran ◽

Vijay Thiruvenkatam

Keyword(s):

Crystal Structure ◽

Molecular Dynamics ◽

Virtual Screening ◽

Computational Approach ◽

Important Target ◽

Structure Solution ◽

Wet Lab ◽

Approved Drugs ◽

Dynamics Simulations ◽

Fda Approved Drugs

This manuscript shows a detailed computational approach of carefully curated drugs that can potentially act against Nsp15, an endoribonuclease necessary for SARS-CoV2 multiplication. In our work, we have considered maximum resources available on Nsp15 including the recent crystal structure solution of the protein. Owing to the increase in demand for a cure for COVID-19, we have attempted to virtually screen an important target of SARS-CoV2 using the pre-existing FDA approved drugs. The main advantage of our work is our multi-step approach in validating our hits. We have performed initial High Throughput Virtual Screening (HTVS) of 2910 drugs. The top 20 hits were subjected to rigorous molecular docking and molecular dynamics simulations yielding a final number of 5 potential hits. In this global emergency, we have made a humble yet critical attempt by undertaking this work; we hope that our work once published may be of help in carrying out appropriate wet-lab work. We declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere."

Virtual Screening of FDA Approved Drugs Against Nsp15 Endoribonuclease from SARS CoV-2

10.26434/chemrxiv.13265519.v1 ◽

2020 ◽

Author(s):

Althaf Shaik ◽

Nalini Natarajan ◽

Sivapriya Kirubakaran ◽

Vijay Thiruvenkatam

Keyword(s):

Crystal Structure ◽

Molecular Dynamics ◽

Virtual Screening ◽

Computational Approach ◽

Important Target ◽

Structure Solution ◽

Wet Lab ◽

Approved Drugs ◽

Dynamics Simulations ◽

Fda Approved Drugs

This manuscript shows a detailed computational approach of carefully curated drugs that can potentially act against Nsp15, an endoribonuclease necessary for SARS-CoV2 multiplication. In our work, we have considered maximum resources available on Nsp15 including the recent crystal structure solution of the protein. Owing to the increase in demand for a cure for COVID-19, we have attempted to virtually screen an important target of SARS-CoV2 using the pre-existing FDA approved drugs. The main advantage of our work is our multi-step approach in validating our hits. We have performed initial High Throughput Virtual Screening (HTVS) of 2910 drugs. The top 20 hits were subjected to rigorous molecular docking and molecular dynamics simulations yielding a final number of 5 potential hits. In this global emergency, we have made a humble yet critical attempt by undertaking this work; we hope that our work once published may be of help in carrying out appropriate wet-lab work. We declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere."