Can Non-steroidal Anti-inflammatory Drugs Affect the Interaction Between Receptor Binding Domain of SARS-COV-2 Spike and the Human ACE2 Receptor? A Computational Biophysical Study

González, Lenin; Lossada, Carla; Fernández-Materán, Francelys V.; Paz, José Luis Castro de; Vera-Villalobos, Joan; Alvarado, Ysaías J.

doi:10.3389/fphy.2020.587606

Cited by 8 publications

(24 citation statements)

References 90 publications

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“…The host nuclear import system can be bound and sequestered by pathogens such as SARS-CoV-2 allowing transportation of viral proteins to the host nucleus leading to increased viral replication [ [12] , [13] , [14] , [15] ]. Additionally, we also consider the multi-functional helicase (nsp13) of SARS-CoV-2 responsible for viral replication (PDB: 6ZSL ) [ [16] , [17] , [18] ], and the main protease (Mpro) of SARS-CoV-2 (PDB: 6LU7 ) as it is a key enzyme of coronaviruses and has a fundamental role in mediating viral replication and transcription, making it an attractive target for drugs [ 11 , [19] , [20] , [21] , [22] ]. All structures were obtained in PDB format from the RCSB protein database ( https://www.rcsb.org/ ).…”

Section: Methodsmentioning

confidence: 99%

“…The binding constant K from the binding free energy was calculated as described [ 11 , 25 ] from the following equation:

…”

Section: Methodsmentioning

confidence: 99%

“…However, it has also been reported that ivermectin has a potentially inhibitory effect against other viruses such as flaviviruses by blocking the NS3 helicase [ 10 ]. Additionally, it has been reported that it can dock in a thermodynamically favorable manner, and with theoretical potential to inhibit other structural and functional proteins associated with SARS-CoV-2 [ 11 ]. This diversity of possible targets for ivermectin and the fact that there are very few comparative reports in the SARS-CoV-2 on the behavior of homologs, represents an area of opportunity to contribute with theoretical studies that provide data applicable to the design of drugs and targeted at this new viral strain of interest in global public health.…”

Section: Introductionmentioning

confidence: 99%

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Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach

González

Hurtado-León

Lossada

et al. 2021

Biophysical Chemistry

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The SARS-CoV-2 pandemic has accelerated the study of existing drugs. The mixture of homologs called ivermectin (avermectin-B1a [HB1a] + avermectin-B1b [HB1b]) has shown antiviral activity against SARS-CoV-2 in vitro . However, there are few reports on the behavior of each homolog. We investigated the interaction of each homolog with promising targets of interest associated with SARS-CoV-2 infection from a biophysical and computational-chemistry perspective using docking and molecular dynamics. We observed a differential behavior for each homolog, with an affinity of HB1b for viral structures, and of HB1a for host structures considered. The induced disturbances were differential and influenced by the hydrophobicity of each homolog and of the binding pockets. We present the first comparative analysis of the potential theoretical inhibitory effect of both avermectins on biomolecules associated with COVID-19, and suggest that ivermectin through its homologs, has a multiobjective behavior.

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Section: Methodsmentioning

confidence: 99%

“…The binding constant K from the binding free energy was calculated as described [ 11 , 25 ] from the following equation:

…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach

González

Hurtado-León

Lossada

et al. 2021

Biophysical Chemistry

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show abstract

“…The host nuclear import system can be bound and sequestered by pathogens such as SARS-CoV-2 allowing transportation of viral proteins to the host nucleus leading to increased viral replication [25] , [26] , [27] , [28] , [29] . Additionally, we also consider the multi-functional helicase (nsp13) of SARS-CoV-2 responsible for viral replication (PDB: 6ZSL) [30] , [31] , [32] , and the main protease (Mpro) of SARS-CoV-2 (PDB: 6LU7) as it is a key enzyme of coronaviruses and has a fundamental role in mediating viral replication and transcription, making it an attractive target for drugs [33] , [34] , [35] , [36] , [37] . All structures were obtained in PDB format from the RCSB Protein Data Bank ( https://www.rcsb.org/ ).…”

Section: Methodsmentioning

confidence: 99%

“…Finally, we obtained a minimized energy structure at 100 ns and 10 instantaneous structures every 10 ns. All MD simulations and additional adjustments were performed using cosgene/myPresto [8] , [36] , [49] . Cosgene/myPresto is available at http://presto.protein.osaka-u.ac.jp/myPresto4/index_e.html .…”

Section: Methodsmentioning

confidence: 99%

Structural deformability induced in proteins of potential interest associated with COVID-19 by binding of homologues present in ivermectin: Comparative study based in elastic networks models

González

Hurtado-León

Lossada

et al. 2021

Journal of Molecular Liquids

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The COVID-19 pandemic has accelerated the study of the potential of multi-target drugs (MTDs). The mixture of homologues called ivermectin (avermectin-B1a + avermectin-B1b) has been shown to be a MTD with potential antiviral activity against SARS-CoV-2 in vitro . However, there are few reports on the effect of each homologue on the flexibility and stiffness of proteins associated with COVID-19, described as ivermectin targets. We observed that each homologue was stably bound to identified proteinsthe proteins studied and were able to induce detectable changes with Elastic Network Models (ENMs). The perturbations induced by each homologue were characteristic of each compound and, in turn, were represented by a disruption of native intramolecular networks (interactions between residues). The homologues were able to slightly modify the conformation and stability of the connection points between the Cα atoms of the residues that make up the structural network of proteins (nodes), compared to free proteins. Each homologue was able to modified differently the distribution of quasi-rigid regions of the proteins, which could theoretically alter their biological activities. These results could provide a biophysical-computational view of the potential MTD mechanism that has been reported for ivermectin.

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Risk of SARS‐CoV‐2 Infection and COVID‐19 Severity Associated With Exposure to Nonsteroidal Anti‐Inflammatory Drugs: Systematic Review and Meta‐Analysis

Prada

Santos

Baião

et al. 2021

The Journal of Clinical Pharma

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Non‐steroidal anti‐inflammatory drugs (NSAIDs) were thought to increase the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) virus entrance into cells. Hence, it was suggested in the media that NSAIDs could lead to a higher risk of infection and/or disease severity. To determine the existence or absence of this association, we aimed to systematically evaluate the risk of SARS‐CoV‐2 infection and mortality and the risk of severe coronavirus disease 2019 (COVID‐19) associated with previous exposure to NSAIDs. MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE were searched in February 2021 for controlled studies. The results were calculated through random‐effect meta‐analyses and reported in terms of odds ratio (OR) with 95% confidence intervals (CI). Heterogeneity was assessed with I 2 test. Eleven studies were included, comprising a total of 683 715 patients. NSAID exposure did not increase the risk of having a positive test for SARS‐CoV‐2 infection (OR 0.97, 95% CI 0.85–1.11, I 2 = 24%, five studies). The exposure to NSAIDs did not increase the risk of severe/critical COVID‐19 disease (OR 0.92, 95% CI 0.80–1.05, I 2 = 0%, 5 studies) nor all‐cause mortality among patients with COVID‐19 (OR 0.86, 95% CI 0.75–0.99, I 2 = 14%, four studies). Our data did not suggest that exposure to NSAIDs increases the risk of having SARS‐CoV‐2 infection or increases the severity of COVID‐19 disease. Also, the fragility of the studies included precludes definite conclusions and highlights the need for further robust data. Systematic review registration number : CRD42020216806 This article is protected by copyright. All rights reserved

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Can Non-steroidal Anti-inflammatory Drugs Affect the Interaction Between Receptor Binding Domain of SARS-COV-2 Spike and the Human ACE2 Receptor? A Computational Biophysical Study

Cited by 8 publications

References 90 publications

Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach

Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach

Structural deformability induced in proteins of potential interest associated with COVID-19 by binding of homologues present in ivermectin: Comparative study based in elastic networks models

Risk of SARS‐CoV‐2 Infection and COVID‐19 Severity Associated With Exposure to Nonsteroidal Anti‐Inflammatory Drugs: Systematic Review and Meta‐Analysis

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