Molecular Docking and Molecular Dynamic Study of Two Viral Proteins Associated with SARS-CoV-2 with Ivermectin

Paz, Lenin Andres Gonzalez; Lossada, Carla; Moncayo, Luis; Romero, Freddy; Paz, José Luis Castro de; Vera-Villalobos, Joan; Pérez, Aleivi; San‐Blas, Ernesto; Alvarado, Ysaías J.

doi:10.20944/preprints202004.0334.v1

Cited by 12 publications

(9 citation statements)

References 35 publications

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“…Ivermectin is an anti‐parasitic drug the usage of which extended from veterinary medicine to humans. 103 In addition to in silico studies 104 involving the interactions between ivermectin and SARS‐CoV‐2 3CL pro , an in vitro study is performed by Caly et al 92 indicating ivermectin's capability to reduce viral RNA. Ivermectin (NCT04668469) has recently been evaluated for the clinical trials.…”

Section: Resultsmentioning

confidence: 99%

Repurposing of FDA‐approved drugs against active site and potential allosteric drug‐binding sites of COVID‐19 main protease

et al. 2021

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The novel coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS‐CoV‐2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (M pro ), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on M pro that can be evaluated as drug targets besides the active site. Then, Food and Drug Administration (FDA)‐approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. Fourteen best molecule hits for the active site of M pro are determined. Six of these also exhibit high docking scores for the potential allosteric regions. Full‐atom molecular dynamics simulations with MM‐GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆ G bind ) values. ∆ G bind values reach −52.06 kcal/mol for the active site, −51.08 kcal/mol for the potential allosteric site 1, and − 42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin, and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as M pro inhibitor candidates to be evaluated against SARS‐CoV‐2 infections.

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Section: Resultsmentioning

confidence: 99%

Repurposing of FDA‐approved drugs against active site and potential allosteric drug‐binding sites of COVID‐19 main protease

et al. 2021

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“…The first studies faced the problem that the crystallographic structure of SARS-CoV-2 3CLpro was not available and hence relied on homology modeling; 175 , 176 the experimental resolution of the 3CLpro structure boosted a huge increase in molecular docking studies. 176 − 180 , 192 …”

Section: Sars-cov-2 Proteasesmentioning

confidence: 99%

“…Chloroquine was also found to stably bind 3CLPro, suggesting that protease inhibition could represent a secondary mechanism of action of this potential drug. 122 González-Paz et al 192 performed a blind-docking study to predict the binding of the B1a and B1b forms of the wide-range antiparasitic drug ivermectin ( Figure 10 ) to 3CLpro, suggesting that ivermectin B1a binds with a higher affinity than ivermectin B1b. Lobo-Galo et al 180 used a multiscale approach in which blind docking was first used to pinpoint the principal potential binding cavities, most often corresponding to the active site, and this region was subsequently selected for further focused docking.…”

Section: Sars-cov-2 Proteasesmentioning

confidence: 99%

Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

et al. 2020

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The emergence in late 2019 of the coronavirus SARS-CoV-2 has resulted in the breakthrough of the COVID-19 pandemic that is presently affecting a growing number of countries. The development of the pandemic has also prompted an unprecedented effort of the scientific community to understand the molecular bases of the virus infection and to propose rational drug design strategies able to alleviate the serious COVID-19 morbidity. In this context, a strong synergy between the structural biophysics and molecular modeling and simulation communities has emerged, resolving at the atomistic level the crucial protein apparatus of the virus and revealing the dynamic aspects of key viral processes. In this Review, we focus on how in silico studies have contributed to the understanding of the SARS-CoV-2 infection mechanism and the proposal of novel and original agents to inhibit the viral key functioning. This Review deals with the SARS-CoV-2 spike protein, including the mode of action that this structural protein uses to entry human cells, as well as with nonstructural viral proteins, focusing the attention on the most studied proteases and also proposing alternative mechanisms involving some of its domains, such as the SARS unique domain. We demonstrate that molecular modeling and simulation represent an effective approach to gather information on key biological processes and thus guide rational molecular design strategies.

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“…On the other hand, Ivermectin can bind to 3CL protease and HR2 protein, blocking viral replication. (15)…”

Section: Discussionmentioning

confidence: 99%

The use of compassionate Ivermectin in the management of symptomatic outpatients and hospitalized patients with clinical diagnosis of COVID-19 at the Medical Center Bournigal and the Medical Center Punta Cana, Rescue Group, Dominican Republic, from may 1 to august 10, 2020

Morgenstern¹,

Jn²,

et al. 2020

Preprint

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Summary: No antiviral has been shown to reduce mortality in SARS-COV-2 patients to date. In the present observational and retrospective report, 3,099 patients with a definitive or highly probable diagnosis of infection due to COVID-19 were evaluated between May 1st to August 10th, 2020, at Centro Medico Bournigal (CMBO) and Centro Medico Punta Cana (CMPC), and all received compassionate treatment with Ivermectin. A total of 2,706 (87.3%) were discharged for outpatient treatment, all with mild severity of the infection. In 2,688 (99.33%) with outpatient treatment, the disease did not progress to warrant further hospitalization and there were no deaths. In 16 (0.59%) with outpatient treatment, it was necessary their subsequent hospitalization to a room without any death. In 2 (0.08%) with outpatient treatment, it was necessary their admission to the Intensive Care Unit (ICU) and 1 (0.04%) patient died. There were 411 (13.3%) patients hospitalized, being admitted at a COVID-19 room with a moderate disease 300 (9.7%) patients of which 3 (1%) died; and with a severe to critical disease were hospitalized in the ICU 111 (3.6%), 34 (30.6%) of whom died. The mortality percentage of patients admitted to the ICU of 30.6%, is similar with the percentage found in the literature of 30.9%. Total mortality was 37 (1.2%) patients, which is much lower than that reported in world statistics, which are around 3%.

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Molecular Docking and Molecular Dynamic Study of Two Viral Proteins Associated with SARS-CoV-2 with Ivermectin

Cited by 12 publications

References 35 publications

Repurposing of FDA‐approved drugs against active site and potential allosteric drug‐binding sites of COVID‐19 main protease

Repurposing of FDA‐approved drugs against active site and potential allosteric drug‐binding sites of COVID‐19 main protease

Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

The use of compassionate Ivermectin in the management of symptomatic outpatients and hospitalized patients with clinical diagnosis of COVID-19 at the Medical Center Bournigal and the Medical Center Punta Cana, Rescue Group, Dominican Republic, from may 1 to august 10, 2020

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