In silico prediction of potential inhibitors for the main protease of SARS-CoV-2 using molecular docking and dynamics simulation based drug-repurposing

Kumar, Yogesh; Singh, Harvijay; Patel, Chirag

doi:10.1016/j.jiph.2020.06.016

Cited by 194 publications

(149 citation statements)

References 44 publications

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“…4 Coronavirus belongs to the family of Coronavirinae, the phylogenetic analysis of COVID-19 genome shows that the virus is closely related to the Bat-SL-CoV and without any divergence at the genomic level. 5 It mainly infects the respiratory system and is transmitted via respiratory droplets primarily through close contact. The virus could result in mild illness up to a critical care condition, which requires specialized treatment at intensive care units.…”

Section: Introductionmentioning

confidence: 99%

<p>Predictors of Severity and Co-Infection Resistance Profile in COVID-19 Patients: First Report from Upper Egypt</p>

Ramadan¹,

Mahmoud²,

Aburahma³

et al. 2020

IDR

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Background: The emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in a worldwide devastating effect with a diagnostic challenge. Identifying risk factors of severity aids in assessment for the need of early hospitalization. We aimed to demonstrate, for the first time, the clinical, laboratory and radiological characteristics of coronavirus disease 2019 (COVID-19) patients, to identify the predictors of severity and to describe the antimicrobial resistance profile in patients from Upper Egypt. Materials and Methods: Demographic characters, clinical presentations, laboratory, and radiological data were recorded and analyzed. Presence of other respiratory microorganisms and their sensitivity patterns were identified using the VITEK2 system. Resistance-associated genes were tested by PCR. Results: The study included 260 COVID-19 patients. The majority were males (55.4%) aged between 51 and 70 years. Hypertension, diabetes, and ischemic heart disease were common comorbidities. Main clinical manifestations were fever (63.8%), cough (57.7%), dyspnea (40%) and fatigue (30%). According to severity, 51.5% were moderate, 25.4% mild and 23% severe/critical. Lymphopenia, elevated CRP, ferritin, and D-dimer occurred in all patients with significantly higher value in the severe group. Age >53 years and elevated ferritin ≥484 ng/mL were significant risk factors for severity. About 10.7% of the COVID-19 patients showed bacterial and/or fungal infections. Klebsiella pneumoniae, Acinetobacter baumannii, and Staphylococcus aureus were the predominant isolated bacteria while Candida albicans and Candida glabrata were the predominant isolated fungi. All Staphylococci were methicillin-resistant and carried the mecA gene. Gram-negative isolates were multidrug-resistant and carried different resistance-associated genes, including NDM-1, KPC, TEM, CTX-M, and SHV. Conclusion: Older age and elevated serum ferritin were significant risk factors for severe COVID-19. Bacterial co-infection and multidrug resistance among patients with COVID-19 in Upper Egypt is common. Testing for presence of other co-infecting agents should be considered, and prompt treatment should be carried out according to the antimicrobial sensitivity reports.

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Section: Introductionmentioning

confidence: 99%

<p>Predictors of Severity and Co-Infection Resistance Profile in COVID-19 Patients: First Report from Upper Egypt</p>

Ramadan¹,

Mahmoud²,

Aburahma³

et al. 2020

IDR

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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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“…Besides the repurposing efforts, in silico molecular docking and simulations studies revealed potential synthetic and naturally occurring compounds in herbal and medicinal plants that interact with both viral and host target proteins (Amin and Abbas, 2020;Maurya et al, 2020;da Silva et al, 2020). These compounds targeted the SARS-CoV-2 spike proteins (Abdelli et al, 2020;Kiran et al, 2020;Maurya et al, 2020;Zhang et al, 2005) Mpro (Ibrahim et al, 2020a;Jin et al, 2020;Joshi et al, 2020;Kumar et al, 2020;Narkhede et al, 2020) and 3CLpro proteases (Gyebi et al, 2020;Ul Qamar et al, 2020), host ACE2 (Benarba and Pandiella, 2020;Maurya et al, 2020) and host TMPRSS2 (Benarba and Pandiella, 2020; Rahman et al, 2020). In addition to the docking scores, few of these studies have determined drug-like properties in silico (Narkhede et al, 2020) and have reported activity of compounds in functional assays in vitro (Jin et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Current targets and drug candidates for prevention and treatment of SARS-CoV-2 (COVID-19) infection

Goyal¹,

Majeed²,

Tonk³

et al. 2020

Reviews in Cardiovascular Medicine

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Angiotensin-converting enzyme 2 (ACE2), the host cellbinding site for SAR-CoV-2, poses twofold drug development problems. First, the role of ACE2 itself is still a matter of investigation, and no specific drugs are available targeting ACE2. Second, as a consequence of SARS-CoV-2 interaction with ACE2, there is an impairment of the renin-angiotensin system (RAS) involved in the functioning of vital organs like the heart, kidney, brain, and lungs. In developing antiviral drugs for COVID-19, ACE2, RNAdependent RNA polymerase (RdRp), and the specific enzymes involved in the viral and cellular gene expression have been the primary targets. SARS-CoV-2 being a new virus with unusually high mortality, there has been a need to get medicines in an emergency, and the drug repurposing has been a primary strategy. Considering extensive mortality and morbidity throughout the world, we have made a maiden attempt to discover the drugs interacting with RAS and identify the lead compounds from herbal plants using molecular docking. Both host ACE2 and viral RNA-dependent RNA polymerase (RdRp) and ORF8 appear to be the primary targets for the treatment of COVID-19. While the drug repurposing of currently approved drugs seems to be one strategy for the treatment of COVID-19, purposing phytochemicals may be another essential strategy for discovering lead compounds. Using in silico molecular docking, we have identified a few phytochemicals that may provide insights into designing herbal and synthetic therapeutics to treat COVID-19.

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In silico prediction of potential inhibitors for the main protease of SARS-CoV-2 using molecular docking and dynamics simulation based drug-repurposing

Cited by 194 publications

References 44 publications

<p>Predictors of Severity and Co-Infection Resistance Profile in COVID-19 Patients: First Report from Upper Egypt</p>

<p>Predictors of Severity and Co-Infection Resistance Profile in COVID-19 Patients: First Report from Upper Egypt</p>

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

Current targets and drug candidates for prevention and treatment of SARS-CoV-2 (COVID-19) infection

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