scholarly journals Pseudo-Dipeptide Bearing α,α-Difluoromethyl Ketone Moiety as Electrophilic Warhead with Activity against Coronaviruses

2021 ◽  
Vol 22 (3) ◽  
pp. 1398
Author(s):  
Andrea Citarella ◽  
Davide Gentile ◽  
Antonio Rescifina ◽  
Anna Piperno ◽  
Barbara Mognetti ◽  
...  
Keyword(s):  
Antiviral Agent ◽  
In Silico Analysis ◽  
Lung Fibroblasts ◽  
Human Embryonic Lung ◽  
Main Protease ◽  
Low Cytotoxicity ◽  
Human Coronaviruses ◽  
Dynamics Simulations ◽  
Micromolar Range ◽  
Viral Cytopathic Effect

The synthesis of α-fluorinated methyl ketones has always been challenging. New methods based on the homologation chemistry via nucleophilic halocarbenoid transfer, carried out recently in our labs, allowed us to design and synthesize a target-directed dipeptidyl α,α-difluoromethyl ketone (DFMK) 8 as a potential antiviral agent with activity against human coronaviruses. The ability of the newly synthesized compound to inhibit viral replication was evaluated by a viral cytopathic effect (CPE)-based assay performed on MCR5 cells infected with one of the four human coronaviruses associated with respiratory distress, i.e., hCoV-229E, showing antiproliferative activity in the micromolar range (EC50 = 12.9 ± 1.22 µM), with a very low cytotoxicity profile (CC50 = 170 ± 3.79 µM, 307 ± 11.63 µM, and 174 ± 7.6 µM for A549, human embryonic lung fibroblasts (HELFs), and MRC5 cells, respectively). Docking and molecular dynamics simulations studies indicated that 8 efficaciously binds to the intended target hCoV-229E main protease (Mpro). Moreover, due to the high similarity between hCoV-229E Mpro and SARS-CoV-2 Mpro, we also performed the in silico analysis towards the second target, which showed results comparable to those obtained for hCoV-229E Mpro and promising in terms of energy of binding and docking pose.

scholarly journals The Repurposed Drugs Suramin and Quinacrine Cooperatively Inhibit SARS-CoV-2 3CLpro In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 873
Author(s):  
Raphael J. Eberle ◽  
Danilo S. Olivier ◽  
Marcos S. Amaral ◽  
Ian Gering ◽  
Dieter Willbold ◽  
...  
Keyword(s):  
Binding Mode ◽  
Drug Candidates ◽  
Main Protease ◽  
Ic50 Values ◽  
Repurposed Drugs ◽  
Antiparasitic Drugs ◽  
Inhibitory Potential ◽  
Dynamics Simulations ◽  
Micromolar Range

Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CLpro). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC50 values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CLpro but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CLpro. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.

scholarly journals Rutin Is a Low Micromolar Inhibitor of SARS-CoV-2 Main Protease 3CLpro: Implications for Drug Design of Quercetin Analogs

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 375
Author(s):  
Bruno Rizzuti ◽  
Fedora Grande ◽  
Filomena Conforti ◽  
Ana Jimenez-Alesanco ◽  
Laura Ceballos-Laita ◽  
...  
Keyword(s):  
Drug Design ◽  
Simulation Techniques ◽  
Model Combining ◽  
Main Protease ◽  
Experimental Spectroscopy ◽  
Dynamics Simulations ◽  
Catalytic Dyad ◽  
Micromolar Range

The pandemic, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has stimulated the search for antivirals to tackle COVID-19 infection. Molecules with known pharmacokinetics and already approved for human use have been demonstrated or predicted to be suitable to be used either directly or as a base for a scaffold-based drug design. Among these substances, quercetin is known to be a potent in vitro inhibitor of 3CLpro, the SARS-CoV-2 main protease. However, its low in vivo bioavailability calls for modifications to its molecular structure. In this work, this issue is addressed by using rutin, a natural flavonoid that is the most common glycosylated conjugate of quercetin, as a model. Combining experimental (spectroscopy and calorimetry) and simulation techniques (docking and molecular dynamics simulations), we demonstrate that the sugar adduct does not hamper rutin binding to 3CLpro, and the conjugated compound preserves a high potency (inhibition constant in the low micromolar range, Ki = 11 μM). Although showing a disruption of the pseudo-symmetry in the chemical structure, a larger steric volume and molecular weight, and a higher solubility compared to quercetin, rutin is able to associate in the active site of 3CLpro, interacting with the catalytic dyad (His41/Cys145). The overall results have implications in the drug-design of quercetin analogs, and possibly other antivirals, to target the catalytic site of the SARS-CoV-2 3CLpro.

scholarly journals Potential of NO donor furoxan as SARS-CoV-2 main protease (Mpro) inhibitors: in silico analysis

2020 ◽  
pp. 1-15 ◽  
Author(s):  
Abdullah G. Al-Sehemi ◽  
Mehboobali Pannipara ◽  
Rishikesh S. Parulekar ◽  
Omkar Patil ◽  
Prafulla B. Choudhari ◽  
...  
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
No Donor ◽  
Main Protease ◽  
Silico Analysis

scholarly journals In silico analysis of Phyllanthus amarus phytochemicals as potent drugs against SARS-CoV-2 main protease

2021 ◽  
pp. 100159
Author(s):  
T.P. Krishna Murthy ◽  
Trupthi Joshi ◽  
Shivani Gunnan ◽  
Nidhi Kulkarni ◽  
Priyanka V ◽  
...  
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
Phyllanthus Amarus ◽  
Main Protease ◽  
Silico Analysis

Genotoxic Effect of a New Water-Soluble Fullerene Derivative C70 and its Effect on the Transcriptional Activity of Genes that Regulate the Cell Cycle, DNA Repair and Apoptosis

2021 ◽  
Vol 1031 ◽  
pp. 222-227
Author(s):  
Ekaterina A. Savinova ◽  
Elizaveta S. Ershova ◽  
Olga A. Kraevaya ◽  
Pavel A. Troshin ◽  
S.V. Kostyuk
Keyword(s):  
Cell Cycle ◽  
Transcriptional Activity ◽  
Water Soluble ◽  
Lung Fibroblasts ◽  
Fullerene Derivative ◽  
Embryonic Lung ◽  
Dna Breaks ◽  
Human Embryonic Lung ◽  
Fullerene Derivatives ◽  
Cellular Dna

It is important to take into consideration the new fullerene derivatives genotoxicity. In the present is study, we analyzed the new water-soluble fullerene C70 (F350) effects on the human embryonic lung fibroblasts (HELF) oxidative damage and DNA breaks. We found that the studied compound causes cellular DNA damage and affects the transcriptional activity of cell cycle and cell apoptosis regulating genes.

scholarly journals In Silico Analysis of the Subtype Selective Blockage of KCNA Ion Channels through the µ-Conotoxins PIIIA, SIIIA, and GIIIA

Marine Drugs ◽  
2019 ◽  
Vol 17 (3) ◽  
pp. 180 ◽  
Author(s):  
Desirée Kaufmann ◽  
Alesia Tietze ◽  
Daniel Tietze
Keyword(s):  
In Silico Analysis ◽  
Binding Mode ◽  
Dynamic Simulations ◽  
Drug Candidates ◽  
Toxin Binding ◽  
Subtype Specificity ◽  
Pore Blockage ◽  
Natural Peptide ◽  
Dynamics Simulations ◽  
Subtype Selective

Understanding subtype specific ion channel pore blockage by natural peptide-based toxins is crucial for developing such compounds into promising drug candidates. Herein, docking and molecular dynamics simulations were employed in order to understand the dynamics and binding states of the µ-conotoxins, PIIIA, SIIIA, and GIIIA, at the voltage-gated potassium channels of the KV1 family, and they were correlated with their experimental activities recently reported by Leipold et al. Their different activities can only adequately be understood when dynamic information about the toxin-channel systems is available. For all of the channel-bound toxins investigated herein, a certain conformational flexibility was observed during the molecular dynamic simulations, which corresponds to their bioactivity. Our data suggest a similar binding mode of µ-PIIIA at KV1.6 and KV1.1, in which a plethora of hydrogen bonds are formed by the Arg and Lys residues within the α-helical core region of µ-PIIIA, with the central pore residues of the channel. Furthermore, the contribution of the K+ channel’s outer and inner pore loops with respect to the toxin binding. and how the subtype specificity is induced, were proposed.

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