New Anti SARS-Cov-2 Targets for Quinoline Derivatives Chloroquine and Hydroxychloroquine

Gentile, Davide; Fuochi, Virginia; Rescifina, Antonio; Furneri, Pio Maria

doi:10.3390/ijms21165856

Cited by 31 publications

(31 citation statements)

References 114 publications

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“…Flexible ligand docking experiments, successfully used in our previous work [ 31 , 59 , 60 , 61 , 62 , 63 , 64 ], were performed employing AutoDock 4.2.6 software implemented in YASARA (v. 20.10.4, YASARA Biosciences GmbH, Vienna, Austria) [ 65 , 66 ], using the three-dimensional crystal structure of hCoV-229E M pro (PDB ID: 1P9S), the three-dimensional crystal structure of SARS-CoV-2 M pro in complex with an inhibitor N3 PRD_002214 (PDB ID: 6LU7), both obtained from the Protein Data Bank (PDB, ), and the Lamarckian genetic algorithm (LGA). The covalent bond between the Cys145 residue and the crystallized ligand has been eliminated.…”

Section: Methodsmentioning

confidence: 99%

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

Citarella

Gentile

Rescifina

et al. 2021

IJMS

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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.

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Section: Methodsmentioning

confidence: 99%

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

Citarella

Gentile

Rescifina

et al. 2021

IJMS

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“…The preparation of the structures of the molecules and the protein and all parameters for docking experiments and molecular dynamics simulations were conducted following the procedures previously reported by us [ 14 , 15 , 16 , 27 , 34 ]. The 3D structures of the BoNT LC/A−G (PDB ID: 4HEV, 1F82, 2QN0, 2FPQ, 1T3A, 2A8A, and 1ZB7) used for the experiments were obtained from the Protein Data Bank.…”

Section: Methodsmentioning

confidence: 99%

“…Nowadays, CAMD and computational chemistry are essential aspects of drug design and have been used to follow atom-by-atom interaction and reactivity [ 11 , 12 ]. From hit identification to lead optimization and beyond, approaches such as structure-based, ligand-based, and virtual screening are widely used by our research group to support drug discovery efforts [ 13 , 14 ]. Generally, these methods can be divided into structure-based and ligand-based drug design.…”

Section: Introductionmentioning

confidence: 99%

An Integrated Pharmacophore/Docking/3D-QSAR Approach to Screening a Large Library of Products in Search of Future Botulinum Neurotoxin A Inhibitors

Gentile

Floresta

Patamia

et al. 2020

IJMS

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Botulinum toxins are neurotoxins produced by Clostridium botulinum. This toxin can be lethal for humans as a cause of botulism; however, in small doses, the same toxin is used to treat different conditions. Even if the therapeutic doses are effective and safe, the adverse reactions could be local and could unmask a subclinical impairment of neuromuscular transmissions. There are not many cases of adverse events in the literature; however, it is possible that sometimes they do not occur as they are transient and, if they do occur, there is no possibility of a cure other than to wait for the pharmacological effect to end. Inhibition of botulinum neurotoxin type A (BoNT/A) effects is a strategy for treating botulism as it can provide an effective post-exposure remedy. In this paper, 13,592,287 compounds were screened through a pharmacophore filter, a 3D-QSAR model, and a virtual screening; then, the compounds with the best affinity were selected. Molecular dynamics simulation studies on the first four compounds predicted to be the most active were conducted to verify that the poses foreseen by the docking were stable. This approach allowed us to identify compounds with a calculated inhibitory activity in the range of 316–500 nM.

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“…Nonetheless, modeling of the SARS-CoV-2 NSP14 active site revealed that remdesivir would create a steric clash, suggesting a less efficient excision of this drug [ 124 ]. Gentile et al proposed that chloroquine and hydoxychloroqiune could interact in the ExoN and SAM-MTase activity site [ 125 ]. SARS-CoV-2 NSP10 and NSP16 mutations were detected in some patients and in silico models suggest that it could have an impact on the stability of the complex [ 116 , 126 ].…”

Section: Structure and Function Of The Sars-cov-2 Rna Polymerase: Thementioning

confidence: 99%

Analysis of the SARS-CoV-2-host protein interaction network reveals new biology and drug candidates: focus on the spike surface glycoprotein and RNA polymerase

Sokullu

Pinard

Gauthier

et al. 2021

Expert Opinion on Drug Discovery

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Introduction : The COVID-19 pandemic originated from the emergence of anovel coronavirus, SARS-CoV-2, which has been intensively studied since its discovery in order to generate the knowledge necessary to accelerate the development of vaccines and antivirals. Of note, many researchers believe there is great potential in systematically identifying host interactors of viral factors already targeted by existing drugs. Areas Covered : Herein, the authors discuss in detail the only available large-scale systematic study of the SARS-CoV-2-host protein–protein interaction network. More specifically, the authors review the literature on two key SARS-CoV-2 drug targets, the Spike surface glycoprotein, and the RNA polymerase. The authors also provide the reader with their expert opinion and future perspectives. Expert opinion : Interactions made by viral proteins with host factors reveal key functions that are likely usurped by the virus and, as aconsequence, points to known drugs that can be repurposed to fight viral infection and collateral damages that can exacerbate various disease conditions in COVID-19.

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New Anti SARS-Cov-2 Targets for Quinoline Derivatives Chloroquine and Hydroxychloroquine

Cited by 31 publications

References 114 publications

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

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

An Integrated Pharmacophore/Docking/3D-QSAR Approach to Screening a Large Library of Products in Search of Future Botulinum Neurotoxin A Inhibitors

Analysis of the SARS-CoV-2-host protein interaction network reveals new biology and drug candidates: focus on the spike surface glycoprotein and RNA polymerase

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