Virtual screening, ADME/Tox predictions and the drug repurposing concept for future use of old drugs against the COVID-19

Hage‐Melim, Lorane Izabel da Silva; Federico, Leonardo Bruno; Oliveira, Nayana Keyla Seabra de; Francisco, Viviane Cristina Cardoso; Correia, Lenir Cabral; Lima, Henrique Barros de; Gomes, Suzane Quintana; Barcelos, Mariana Pegrucci; Francischini, Isaque Antônio Galindo; Silva, Carlos Henrique Tomich de Paula da

doi:10.1016/j.lfs.2020.117963

Cited by 69 publications

(40 citation statements)

References 49 publications

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“…Also, there are reports regarding small molecules against crucial protein targets that are essential for viral replication with proven potency. Recently, there are several reports cited on designing drugs for SARS-CoV-2 employing in silico virtual screening methods [ [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] ].…”

Section: Introductionmentioning

confidence: 99%

Structure-based drug designing towards the identification of potential anti-viral for COVID-19 by targeting endoribonuclease NSP15

Dhanabalan¹,

Sangeetha²,

Vajravijayan³

et al. 2020

Informatics in Medicine Unlocked

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The world is facing health and economic havoc due to the Corona Virus Disease-2019 (COVID-19) pandemic. Given the number of affected people and the mortality rate, the virus is undoubtedly a serious threat to humanity. By analogy with earlier reports about Severe Acute Respiratory Syndrome (SARS-CoV) and Middle East Respiratory Syndrome (MERS-CoV) - viruses, the novel Coronavirus’ replication mechanism is likely well understood. The structure of an endoribonuclease (NSP15) of SARS-CoV-2 was reported recently. This enzyme is expected to play a crucial role in replication. In this work, attempts were made to identify inhibitors of this enzyme. To achieve the goal, high throughput in silico screening and molecular docking procedures were performed. From an Enamine database of a billion compounds, 3978 compounds with potential antiviral activity were selected for screening and induced fit docking that funneled down to eight compounds with good docking score and docking energy. Detailed analysis of non-covalent interactions at the active site and the apparent match of the molecule with the shape of the binding pocket were assessed. All the compounds show significant interactions for tight binding. Since all the compounds are synthetic with favorable drug-like properties, these may be considered for immediate optimization and downstream applications.

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Section: Introductionmentioning

confidence: 99%

Structure-based drug designing towards the identification of potential anti-viral for COVID-19 by targeting endoribonuclease NSP15

Dhanabalan¹,

Sangeetha²,

Vajravijayan³

et al. 2020

Informatics in Medicine Unlocked

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“…by directly targeting its (Mpro) active site with molecules that competitively bind to the active site "pockets" (Dai et al, 2020;. Studies have been carried out to find suitable inhibitors of Mpro using drug repurposing strategy (Baby et al, 2020;Beck et al, 2020;Bharadwaj et al, 2020;Hage-Melim et al, 2020;Hakmi et al, 2020;Jimenez-Alberto et al, 2020;Kandeel & Al-Nazawi, 2020). Furthermore, various phytochemicals are also proposed as the SARS CoV-2 main protease inhibitors through screening and structure-based design approach (Gorla et al, 2020;Gurung et al, 2020;Mazzini et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Computer aided identification of potential SARS CoV-2 main protease inhibitors from diterpenoids and biflavonoids of Torreya nucifera leaves

Ghosh

Chakraborty

Biswas

et al. 2020

Journal of Biomolecular Structure and Dynamics

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SARS CoV-2 is the causative agent of the pandemic disease COVID-19. There is an urgent need for effective drugs or vaccines which can effectively combat this outbreak. The main protease (Mpro), a key component for the SARS CoV-2 replication, is considered to be one of the important drug targets for developing anti-COVID-19 drugs. This SARS CoV-2 Mpro/cysteine protease has high sequence similarity with the same protease from SARS CoV-1. Previously, it has been shown experimentally that eight diterpenoids and four biflavonoids derived from the leaf of Torreya nucifera show inhibitory effect on the cleavage/catalytic activity of the SARS CoV-1 Mpro. But whether these phytochemicals exhibit any inhibitory effect on SARS CoV-2 Mpro is unclear. To understand this fact, here, we have adopted various in-silico approaches. Diterpenoids and biflavonoids those qualified pharmacological test (hinokiol, amentoflavone, bilobetin and ginkgetin) and two well-known Mpro inhibitors (N3 and lopinavir) were subjected for molecular docking studies. Only three biflavonoids (amentoflavone, bilobetin and ginkgetin) were selected by comparing their binding affinities with N3 and lopinavir. They interacted with two most important catalytic residues of Mpro (His41 and Cys145). Molecular dynamics studies further revealed that these three Mpro-biflavonoid complexes are highly stable and share a similar degree of compactness. Besides, these complexes experience less conformational fluctuations and more expansion than Mpro-N3 and/or Mpro-lopinavir complex. MM-GBSA and H-bond analysis further corroborated these findings. Altogether, our study suggested that these three biflavonoids could possibly inhibit the proteolytic/catalytic activity of SARS CoV-2 Mpro and might be useful for COVID-19 treatment.

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“…Another approach that has been opted for the treatment of COVID-19 is drug repurposing (Baby et al, 2020 ; Beck et al, 2020 ; Bharadwaj et al, 2020 ; Hage-Melim et al, 2020 ; Hakmi et al, 2020 ; Jimenez-Alberto et al, 2020 ; Kandeel & Al-Nazawi, 2020 ; Kumar et al, 2020 ). Drug repurposing is commonly employed to identify potential drugs against different diseases.…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, several drug repurposing options are being considered and are under investigation to control the COVID-19, as there is an urgent requirement for an effective drug or combination of drugs to combat this disease. Several efforts were executed to design novel inhibitors or employ drug repurposing approach to identify anti-COVID-19 drugs, which can act as promising inhibitors against coronavirus protease (Baby et al, 2020 ; Beck et al, 2020 ; Bharadwaj et al, 2020 ; Hage-Melim et al, 2020 ; Hakmi et al, 2020 ; Jimenez-Alberto et al, 2020 ; Kandeel & Al-Nazawi, 2020 ; Kumar et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Potential therapeutic use of corticosteroids as SARS CoV-2 main protease inhibitors: a computational study

Ghosh

Chakraborty

Biswas

et al. 2020

Journal of Biomolecular Structure and Dynamics

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The outbreak of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), represents a pandemic threat to global public health. To date, ∼530,000 people died of this disease worldwide. Presently, researchers/clinicians are adopting the drug repurposing strategy to combat this disease. It has also been observed that some repurposed anti-viral drugs may serve as potent inhibitors of SARS CoV-2 Mpro, a key component of viral replication. Apart from these anti-viral drugs, recently dexamethasone (an important corticosteroid) is effectively used to treat COVID-19 patients. However, the mechanism behind the mode of its action is not so clear. Additionally, the effect of other well-known corticosteroids to control this disease by inhibiting the proteolytic activity of Mpro is ambiguous. In this study, we have adopted computational approaches to understand these aspects. Six well-known corticosteroids (cortisone, hydrocortisone, prednisolone, methylprednisolone, betamethasone and dexamethasone) and two repurposed drugs (darunavir and lopinavir) against COVID-19 were subjected for molecular docking studies. Two of them (betamethasone and dexamethasone) were selected by comparing their binding affinities with selected repurposed drugs toward Mpro. Betamethasone and dexamethasone interacted with both the catalytic residues of Mpro (His41 and Cys145). Molecular dynamics studies further revealed that these two Mpro-corticosteroid complexes are more stable, experience less conformational fluctuations and more compact than Mpro-darunavir/lopinavir complexes. These findings were additionally validated by MM-GBSA analysis. This study provides corroboration for execution of anti-COVID-19 activity of dexamethasone. Our study also emphasizes on the use of another important corticosteroid (betamethasone) as potential therapeutic agent for COVID-19 treatment.

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Virtual screening, ADME/Tox predictions and the drug repurposing concept for future use of old drugs against the COVID-19

Cited by 69 publications

References 49 publications

Structure-based drug designing towards the identification of potential anti-viral for COVID-19 by targeting endoribonuclease NSP15

Structure-based drug designing towards the identification of potential anti-viral for COVID-19 by targeting endoribonuclease NSP15

Computer aided identification of potential SARS CoV-2 main protease inhibitors from diterpenoids and biflavonoids of Torreya nucifera leaves

Potential therapeutic use of corticosteroids as SARS CoV-2 main protease inhibitors: a computational study

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