Comparative Computational Study of SARS-CoV-2 Receptors Antagonists from Already Approved Drugs

Docking Studies ◽

World Health ◽

Pharmacokinetic Parameters ◽

Computational Techniques ◽

High Modulation ◽

Approved Drugs ◽

According to the World Health Organisation, on April 12, 2020, the number of confirmed cases of COVID-19 has already exceeded an estimate of 1 600 000 and 105 000 deaths worldwide. Given this, the impact of COVID-19 on humanity cannot be overlooked, and basic research are urgently needed. This research aims to find antagonists already approved for another diseases, that may inhibit activity of the main protease (Mpro) of the SARS-CoV-2 virus, as well as modulate the ACE2 receptors, largely found in lung cells and reduce viral replication by inhibiting NSP12 RNA Polymerase. Docking molecular simulations were realized among a total of 28 ligands published in the literature against COVID-19. Docking studies were made with algorithm of AutoDock Vina 1.1.2 software. A structure-based virtual screening was performed with MTiOpenScreen. Subsequently, the physical-chemical and pharmacokinetic parameters were analyzed with SwissADME in order to select only the most promising ones. Finally, simulations of molecular dynamics with elapsed time of 4 nanoseconds (ns) were analysed in order to better understand the action of drugs to the detriment of the limitations of molecular docking. This work has shown that, in comparative terms, simeprevir, paritaprevir and elbasvir are currently among the most theoretical promising drugs in remission of symptoms from the disease. An important structure that has already been reported in preclinical and clinical studies, in which theoretical results also corroborates high modulation in viral receptors is: indinavir. The second group of promising drugs includes remdesivir, baricitinib and azithromycin, which also have clinical tests. Apparently, the repurposing drugs (hydroxy)chloroquine and chloroquine were not showed effective, as monotherapies, against SARS-CoV-2 virus or ACE2 receptors found predominantly in pneumocytes. Meanwhile, it has not been able to reach conclusive results due to the limitations of computational techniques that do not take into account numerous empirical parameters.

Comparative Computational Study of SARS-CoV-2 Receptors Antagonists from Already Approved Drugs

10.26434/chemrxiv.12044538.v1 ◽

2020 ◽

Author(s):

Micael Davi Lima de Oliveira ◽

Kelson Mota Teixeira de Oliveira

Keyword(s):

Computational Study ◽

Basic Research ◽

Docking Studies ◽

World Health ◽

Pharmacokinetic Parameters ◽

Elapsed Time ◽

Main Protease ◽

Approved Drugs ◽

According to the World Health Organisation, on March 27, 2020, the number of confirmed cases of COVID-19 has already exceeded 509.000 with about of 23.000 deaths worldwide. Given this, the impact of COVID-19 on humanity cannot be overlooked, and basic research are urgently needed. This research aims to find antagonists already approved for another diseases, that may inhibit activity of the main protease (Mpro) of the SARS-CoV-2 virus, as well as modulate the ACE2 receptors, largely found in lung cells and reduce viral replication by inhibiting NSP12 RNA Polymerase. Docking molecular simulations were realized among a total of 28 ligands published in the literature against COVID-19. Docking studies were made with algorithm of AutoDock Vina 1.1.2 software. A structure-based virtual screening was performed with MTiOpenScreen. Subsequently, the physical-chemical and pharmacokinetic parameters were analyzed with SwissADME in order to select only the most promising ones. Finally, simulations of molecular dynamics with elapsed time of 4 nanoseconds (ns) were analysed in order to better understand the action of drugs to the detriment of the limitations of molecular docking. This work has shown that, in comparative terms, Simeprevir, Paritaprevir, Remdesivir and Baricitinib are currently among the most promising in remission of symptoms from the disease. Hydroxy-chloroquine, Chloroquine and Azithromicin were not showed effective, as monotherapies, against COVID-19 or lung cell receptors.

Old Arsenal to Combat New Enemy: Repurposing of Commercially Available FDA Approved Drugs Against Main Protease of SARS-CoV2.

10.26434/chemrxiv.13032578 ◽

2020 ◽

Author(s):

Gagandeep Singh ◽

vishal srivastava ◽

Ritpratik Mishra ◽

Gaurav Goel ◽

Tapan Chaudhuri

Keyword(s):

Drug Design ◽

Binding Free Energy ◽

Md Simulations ◽

Docking Studies ◽

Free Energy Calculations ◽

World Health ◽

Main Protease ◽

Health Organization ◽

Approved Drugs ◽

Potential Inhibitors

In lack of vaccination and therapeutic drugs, the ongoing COVID-19 pandemic affected millions of people, causing 1,018,957 deaths worldwide (World health organization; 1st October 2020). The conventional drug design pipeline for effective and safer drug development is a costly and time-intensive affair. It takes around ten years in general from identifying a clinical candidate to get the approvals for actual applications. An effective way to cut short drug design pipeline in such emergency cases could be the repurposing of already approved drugs against novel targets. Here in this work, we explored the structure-based drug screening approach to find potential inhibitors of SARS-CoV2 main protease (Mpro) from the library of already FDA approved commercially available drugs. The site-specific and blind docking studies, in combination, suggest three potential inhibitors of Mpro, Ergotamine (ZINC000052955754), Nilotinib (ZINC000006716957) and Naldemedine (ZINC000100378061). Molecular dynamics (MD) simulations and binding free energy calculations using the MMPBSA method further reinforced the efficiency of the screened Mpro inhibitor candidates. The work yields enough evidence to conduct rigorous experimental validation of these drugs before utilizing them for the therapeutic management of SARS-CoV2 infection.

Old Arsenal to Combat New Enemy: Repurposing of Commercially Available FDA Approved Drugs Against Main Protease of SARS-CoV2.

10.26434/chemrxiv.13032578.v1 ◽

2020 ◽

Author(s):

Gagandeep Singh ◽

vishal srivastava ◽

Ritpratik Mishra ◽

Gaurav Goel ◽

Tapan Chaudhuri

Keyword(s):

Drug Design ◽

Binding Free Energy ◽

Md Simulations ◽

Docking Studies ◽

Free Energy Calculations ◽

World Health ◽

Main Protease ◽

Health Organization ◽

Approved Drugs ◽

Potential Inhibitors

In lack of vaccination and therapeutic drugs, the ongoing COVID-19 pandemic affected millions of people, causing 1,018,957 deaths worldwide (World health organization; 1st October 2020). The conventional drug design pipeline for effective and safer drug development is a costly and time-intensive affair. It takes around ten years in general from identifying a clinical candidate to get the approvals for actual applications. An effective way to cut short drug design pipeline in such emergency cases could be the repurposing of already approved drugs against novel targets. Here in this work, we explored the structure-based drug screening approach to find potential inhibitors of SARS-CoV2 main protease (Mpro) from the library of already FDA approved commercially available drugs. The site-specific and blind docking studies, in combination, suggest three potential inhibitors of Mpro, Ergotamine (ZINC000052955754), Nilotinib (ZINC000006716957) and Naldemedine (ZINC000100378061). Molecular dynamics (MD) simulations and binding free energy calculations using the MMPBSA method further reinforced the efficiency of the screened Mpro inhibitor candidates. The work yields enough evidence to conduct rigorous experimental validation of these drugs before utilizing them for the therapeutic management of SARS-CoV2 infection.

Comparative docking of SARS-CoV-2 receptors antagonists from repurposing drugs

10.26434/chemrxiv.12044538.v4 ◽

2020 ◽

Author(s):

Micael Davi Lima de Oliveira ◽

Kelson Mota Teixeira de Oliveira

Keyword(s):

World Health ◽

Lung Cells ◽

The Novel ◽

High Modulation ◽

Main Protease ◽

The World ◽

Novel Coronavirus ◽

Viral Receptors ◽

Theoretical Results

According to the World Health Organisation, until 16 June, 2020, the number of confirmed and notified cases of COVID-19 has already exceeded 7.9 million with approximately 434 thousand deaths worldwide. This research aimed to find repurposing antagonists, that may inhibit the activity of the main protease (Mpro) of the SARS-CoV-2 virus, as well as partially modulate the ACE2 receptors largely found in lung cells, and reduce viral replication by inhibiting Nsp12 RNA polymerase. Docking molecular simulations were performed among a total of 60 structures, most of all, published in the literature against the novel coronavirus. The theoretical results indicated that, in comparative terms, paritaprevir, ivermectin, ledipasvir, and simeprevir, are among the most theoretical promising drugs in remission of symptoms from the disease. Furthermore, also corroborate indinavir to the high modulation in viral receptors. The second group of promising drugs includes remdesivir and azithromycin. The repurposing drugs HCQ and chloroquine were not effective in comparative terms to other drugs, as monotherapies, against SARS-CoV-2 infection.

The Impact of Ultraviolet Radiation on the Aetiology and Development of Uveal Melanoma

Cancers ◽

10.3390/cancers13071700 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1700

Author(s):

Melissa Chalada ◽

Charmaine A. Ramlogan-Steel ◽

Bijay P. Dhungel ◽

Christopher J. Layton ◽

Jason C. Steel

Keyword(s):

Risk Factors ◽

Ultraviolet Radiation ◽

Uveal Melanoma ◽

World Health ◽

Genetic Mutations ◽

High Incidence ◽

The World ◽

Uveal melanoma (UM) is currently classified by the World Health Organisation as a melanoma caused by risk factors other than cumulative solar damage. However, factors relating to ultraviolet radiation (UVR) susceptibility such as light-coloured skin and eyes, propensity to burn, and proximity to the equator, frequently correlate with higher risk of UM. These risk factors echo those of the far more common cutaneous melanoma (CM), which is widely accepted to be caused by excessive UVR exposure, suggesting a role of UVR in the development and progression of a proportion of UM. Indeed, this could mean that countries, such as Australia, with high UVR exposure and the highest incidences of CM would represent a similarly high incidence of UM if UVR exposure is truly involved. Most cases of UM lack the typical genetic mutations that are related to UVR damage, although recent evidence in a small minority of cases has shown otherwise. This review therefore reassesses statistical, environmental, anatomical, and physiological evidence for and against the role of UVR in the aetiology of UM.

Riding the waves: the ongoing impact of COVID-19 on a national surgical training cohort

Irish Journal of Medical Science (1971 -) ◽

10.1007/s11845-021-02739-4 ◽

2021 ◽

Author(s):

Orla Hennessy ◽

Amy Lee Fowler ◽

Conor Hennessy ◽

David Brinkman ◽

Aisling Hogan ◽

...

Keyword(s):

Surgical Training ◽

World Health ◽

Training Methods ◽

Viral Spread ◽

Surgical Services ◽

Global Pandemic ◽

Surgical Trainees ◽

Secondary Survey ◽

Abstract Background The World Health Organisation declared a global pandemic on the 11 March 2020 resulting in implementation of methods to contain viral spread, including curtailment of all elective and non-emergent interventions. Many institutions have experienced changes in rostering practices and redeployment of trainees to non-surgical services. Examinations, study days, courses, and conferences have been cancelled. These changes have the potential to significantly impact the education and training of surgical trainees. Aim To investigate the impact of the COVID-19 pandemic on training, educational, and operative experiences of Irish surgical trainees. Methods Surgical trainees were surveyed anonymously regarding changes in working and educational practices since the declaration of the COVID-19 pandemic on 11 March 2020. The survey was circulated in May 2020 to both core and higher RCSI surgical trainees, when restrictions were at level five. Questions included previous and current access to operative sessions as well as operative cases, previous and current educational activities, access to senior-led training, and access to simulation-/practical-based training methods. A repeat survey was carried out in October 2020 when restrictions were at level two. Results Overall, primary and secondary survey response rates were 29% (n = 98/340) and 19.1% (n = 65/340), respectively. At the time of circulation of the second survey, the number of operative sessions attended and cases performed had significantly improved to numbers experienced pre-pandemic (p < 0.0001). Exposure to formal teaching and education sessions returned to pre-COVID levels (p < 0.0001). Initially, 23% of trainees had an examination cancelled; 53% of these trainees have subsequently sat these examinations. Of note 27.7% had courses cancelled, and 97% of these had not been rescheduled. Conclusion Surgical training and education have been significantly impacted in light of COVID-19. This is likely to continue to fluctuate in line with subsequent waves. Significant efforts have to be made to enable trainees to meet educational and operative targets.

“Air pollution arrested not imprisoned”: The impact of laws invoked on Covid-19 city lockdowns

Journal of Clinical Images and Medical Case Reports ◽

10.52768/2766-7820/1275 ◽

2021 ◽

Vol 2 (4) ◽

Author(s):

Emmanuel Mensah Aboagye ◽

◽

Nana Osei Owusu ◽

Keyword(s):

Air Pollution ◽

Environmental Problem ◽

Developed Countries ◽

World Health ◽

Economic Activities ◽

Global Pandemic ◽

Depth Study ◽

The Government ◽

Air pollution continues to be an environmental problem that poses a lot of health risks to the young and aged. Developed countries have invested heavily to curb this environmental problem, causing severe threats to human lives, yet the results do not look convincing. In developing countries, the situation is difficult than they can imagine, resulting in governments borrowing to fight what looks like a lost battle [1-3]. The in-depth study of this environmental menace - air pollution, suggests that the government enacts stringent measures to help fight this battle. This is because air pollution has natural (volcanic eruption) and anthropogenic (human activities) causes. In December 2019, the deadly Coronavirus (Covid-19) outbreak was soon declared as a global pandemic by the World Health Organisation (WHO) [4]. Majority of countries have had their share of the impact of this outbreak. Many countries resorted to city lockdown to strictly control the movement of people and economic activities as recommended by WHO.

Live wildlife trade in markets - a scoping review to inform risk assessment of emerging infectious diseases

10.1101/2021.09.13.21263377 ◽

2021 ◽

Author(s):

Victoria J Brookes ◽

Okta Wismandanu ◽

Etih Sudarnika ◽

Justin A Roby ◽

Lynne Hayes ◽

...

Keyword(s):

Risk Assessment ◽

Infectious Diseases ◽

Scoping Review ◽

Epistemic Uncertainty ◽

Mammalian Species ◽

Emerging Infectious Diseases ◽

World Health ◽

Wildlife Trade ◽

Wet markets are important for food security in many regions worldwide but have come under scrutiny due to their potential role in the emergence of infectious diseases. The sale of live wildlife has been highlighted as a particular risk, and the World Health Organisation has called for the banning of live, wild-caught mammalian species in markets unless risk assessment and effective regulations are in place. Following PRISMA guidelines, we conducted a global scoping review of peer-reviewed information about the sale of live, terrestrial wildlife in markets that are likely to sell fresh food, and collated data about the characteristics of such markets, activities involving live wildlife, the species sold, their purpose, and animal, human, and environmental health risks that were identified. Of the 59 peer-reviewed records within scope, only 25% (n = 14) focussed on disease risks; the rest focused on the impact of wildlife sale on conservation. Although there were some global patterns (for example, the types of markets and purpose of sale of wildlife), there was wide diversity and huge epistemic uncertainty in all aspects associated with live, terrestrial wildlife sale in markets such that the feasibility of accurate assessment of the risk of emerging infectious disease associated with live wildlife trade in markets is limited. Given the value of both wet markets and wildlife trade and the need to support food affordability and accessibility, conservation, public health, and the social and economic aspects of livelihoods of often vulnerable people, there are major information gaps that need to be addressed to develop evidence-based policy in this environment. This review identifies these gaps and provides a foundation from which information for risk assessments can be collected.

Screening of FDA Approved Drugs Against COVID-19 Main Protease: Coronavirus Disease

10.20944/preprints202004.0062.v1 ◽

2020 ◽

Cited By ~ 4

Author(s):

Vijayakumar Balakrishnan ◽

Karthik Lakshminarayanan

Keyword(s):

Vaccine Development ◽

New Drugs ◽

World Health ◽

Wuhan City ◽

Drug Candidates ◽

Human Contact ◽

Main Protease ◽

Potent Drug ◽

Approved Drugs ◽

Fda Approved Drugs

In the end of December 2019, a new strain of coronavirus was identified in the Wuhan city of Hubei province in China. Within a shorter period of time, an unprecedented outbreak of this strain was witnessed over the entire Wuhan city. This novel coronavirus strain was later officially renamed as COVID-19 (Coronavirus disease 2019) by the World Health Organization. The mode of transmission had been found to be human-to-human contact and hence resulted in a rapid surge across the globe where more than 1,100,000 people have been infected with COVID-19. In the current scenario, finding potent drug candidates for the treatment of COVID-19 has emerged as the most challenging task for clinicians and researchers worldwide. Identification of new drugs and vaccine development may take from a few months to years based on the clinical trial processes. To overcome the several limitations involved in identifying and bringing out potent drug candidates for treating COVID-19, in the present study attempts were made to screen the FDA approved drugs using High Throughput Virtual Screening (HTVS). The COVID-19 main protease (COVID-19 Mpro) was chosen as the drug target for which the FDA approved drugs were initially screened with HTVS. The drug candidates that exhibited favorable docking score, energy and emodel calculations were further taken for performing Induced Fit Docking (IFD) using Schrodinger’s GLIDE. From the flexible docking results, the following four FDA approved drugs Sincalide, Pentagastrin, Ritonavir and Phytonadione were identified. In particular, Sincalide and Pentagastrin can be considered potential key players for the treatment of COVID-19 disease.