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1.
BMC Pharmacol Toxicol ; 22(1): 61, 2021 10 21.
Article in English | MEDLINE | ID: covidwho-1477468

ABSTRACT

BACKGROUND: The emergence and rapid spread of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in thelate 2019 has caused a devastating global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19). Although vaccines have been and are being developed, they are not accessible to everyone and not everyone can receive these vaccines. Also, it typically takes more than 10 years until a new therapeutic agent is approved for usage. Therefore, repurposing of known drugs can lend itself well as a key approach for significantly expediting the development of new therapies for COVID-19. METHODS: We have incorporated machine learning-based computational tools and in silico models into the drug discovery process to predict Adsorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiles of 90 potential drugs for COVID-19 treatment identified from two independent studies mainly with the purpose of mitigating late-phase failures because of inferior pharmacokinetics and toxicity. RESULTS: Here, we summarize the cardiotoxicity and general toxicity profiles of 90 potential drugs for COVID-19 treatment and outline the risks of repurposing and propose a stratification of patients accordingly. We shortlist a total of five compounds based on their non-toxic properties. CONCLUSION: In summary, this manuscript aims to provide a potentially useful source of essential knowledge on toxicity assessment of 90 compounds for healthcare practitioners and researchers to find off-label alternatives for the treatment for COVID-19. The majority of the molecules discussed in this manuscript have already moved into clinical trials and thus their known pharmacological and human safety profiles are expected to facilitate a fast track preclinical and clinical assessment for treating COVID-19.


Subject(s)
Antiviral Agents/toxicity , COVID-19/drug therapy , Drug Discovery , Drug Repositioning , Animals , Antiviral Agents/adverse effects , Captopril/therapeutic use , Cardiotoxins/toxicity , Catechols/therapeutic use , Computational Biology , Cytochrome P-450 Enzyme System/metabolism , Drug Discovery/methods , Humans , Indomethacin/therapeutic use , Linezolid/therapeutic use , Liver/drug effects , Mice , Models, Biological , Nitriles/therapeutic use , Rats , Reproduction/drug effects , Software , Valproic Acid/therapeutic use
2.
Biomedicines ; 9(9)2021 Sep 13.
Article in English | MEDLINE | ID: covidwho-1408451

ABSTRACT

Galectin-3 is a carbohydrate-binding protein and the most studied member of the galectin family. It regulates several functions throughout the body, among which are inflammation and post-injury remodelling. Recent studies have highlighted the similarity between Galectin-3's carbohydrate recognition domain and the so-called "galectin fold" present on the N-terminal domain of the S1 sub-unit of the SARS-CoV-2 spike protein. Sialic acids binding to the N-terminal domain of the Spike protein are known to be crucial for viral entry into humans, and the role of Galectin-3 as a mediator of lung fibrosis has long been the object of study since its levels have been found to be abnormally high in alveolar macrophages following lung injury. In this context, the discovery of a double inhibitor may both prevent viral entry and reduce post-infection pulmonary fibrosis. In this study, we use a database of 56 compounds, among which 37 have known experimental affinity with Galectin-3. We carry out virtual screening of this database with respect to Galectin-3 and Spike protein. Several ligands are found to exhibit promising binding affinity and interaction with the Spike protein's N-terminal domain as well as with Galectin-3. This finding strongly suggests that existing Galectin-3 inhibitors possess dual-binding capabilities to disrupt Spike-ACE2 interactions. Herein we identify the most promising inhibitors of Galectin-3 and Spike proteins, of which five emerge as potential dual effective inhibitors. Our preliminary results warrant further in vitro and in vivo testing of these putative inhibitors against SARS-CoV-2 with the hope of being able to halt the spread of the virus in the future.

4.
PLoS Comput Biol ; 17(1): e1008603, 2021 01.
Article in English | MEDLINE | ID: covidwho-1035017

ABSTRACT

The coronavirus causing the COVID-19 pandemic, SARS-CoV-2, uses -1 programmed ribosomal frameshifting (-1 PRF) to control the relative expression of viral proteins. As modulating -1 PRF can inhibit viral replication, the RNA pseudoknot stimulating -1 PRF may be a fruitful target for therapeutics treating COVID-19. We modeled the unusual 3-stem structure of the stimulatory pseudoknot of SARS-CoV-2 computationally, using multiple blind structural prediction tools followed by µs-long molecular dynamics simulations. The results were compared for consistency with nuclease-protection assays and single-molecule force spectroscopy measurements of the SARS-CoV-1 pseudoknot, to determine the most likely conformations. We found several possible conformations for the SARS-CoV-2 pseudoknot, all having an extended stem 3 but with different packing of stems 1 and 2. Several conformations featured rarely-seen threading of a single strand through junctions formed between two helices. These structural models may help interpret future experiments and support efforts to discover ligands inhibiting -1 PRF in SARS-CoV-2.


Subject(s)
Frameshifting, Ribosomal , Nucleic Acid Conformation , SARS-CoV-2/chemistry , COVID-19/virology , Computational Biology , Humans , SARS-CoV-2/genetics
5.
Int J Mol Sci ; 21(9)2020 Apr 28.
Article in English | MEDLINE | ID: covidwho-133237

ABSTRACT

The novel coronavirus whose outbreak took place in December 2019 continues to spread at a rapid rate worldwide. In the absence of an effective vaccine, inhibitor repurposing or de novo drug design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed classical and mixed-solvent molecular dynamics simulations of the main protease (Mpro) enriched by evolutionary and stability analysis of the protein. The results were compared with those for a highly similar severe acute respiratory syndrome (SARS) Mpro protein. In spite of a high level of sequence similarity, the active sites in both proteins showed major differences in both shape and size, indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, analysis of the binding site's conformational changes during the simulation time indicated its flexibility and plasticity, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the protein with respect to flexible loop mutations indicated that the virus' mutability will pose a further challenge to the rational design of small-molecule inhibitors. However, few residues contribute significantly to the protein stability and thus can be considered as key anchoring residues for Mpro inhibitor design.


Subject(s)
Betacoronavirus/enzymology , Cysteine Endopeptidases/chemistry , Drug Design , Protease Inhibitors/pharmacology , Small Molecule Libraries , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Betacoronavirus/genetics , Binding Sites , COVID-19 , Catalytic Domain , Coronavirus 3C Proteases , Coronavirus Infections , Crystallography, X-Ray , Cysteine Endopeptidases/genetics , Drug Evaluation, Preclinical , Evolution, Molecular , Models, Molecular , Molecular Dynamics Simulation , Mutation , Pandemics , Pneumonia, Viral , SARS Virus/enzymology , SARS-CoV-2 , Solvents , Thermodynamics , Viral Nonstructural Proteins/genetics
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