Identifying the natural compound Catechin from tropical mangrove plants as a potential lead candidate against 3CLpro from SARS-CoV-2: An integrated in silico approach.

SARS-CoV-2, a member of beta coronaviruses, is a single-stranded, positive-sense RNA virus responsible for the COVID-19 pandemic. With global fatalities of the pandemic exceeding 4.57 million, it becomes crucial to identify effective therapeutics against the virus. A protease, 3CLpro, is responsible for the proteolysis of viral polypeptides into functional proteins, which is essential for viral pathogenesis. This indispensable activity of 3CLpro makes it an attractive target for inhibition studies. The current study aimed to identify potential lead molecules against 3CLpro of SARS-CoV-2 using a manually curated in-house library of antiviral compounds from mangrove plants. This study employed the structure-based virtual screening technique to evaluate an in-house library of antiviral compounds against 3CLpro of SARS-CoV-2. The library was comprised of thirty-three experimentally proven antiviral molecules extracted from different species of tropical mangrove plants. The molecules in the library were virtually screened using AutoDock Vina, and subsequently, the top five promising 3CLpro-ligand complexes along with 3CLpro-N3 (control molecule) complex were subjected to MD simulations to comprehend their dynamic behaviour and structural stabilities. Finally, the MM/PBSA approach was used to calculate the binding free energies of 3CLpro complexes. Among all the studied compounds, Catechin achieved the most significant binding free energy (-40.3 ± 3.1 kcal/mol), and was closest to the control molecule (-42.8 ± 5.1 kcal/mol), and its complex with 3CLpro exhibited the highest structural stability. Through extensive computational investigations, we propose Catechin as a potential therapeutic agent against SARS-CoV-2. Communicated by Ramaswamy H. Sarma.

Post-COVID Headache: A Literature Review.

PURPOSE OF REVIEW: Post-COVID headache may be unique in presentation and mechanism, often presenting as a new phenotype in patients with a history of a primary headache disorder or resulting in a new headache syndrome in those without history of headache. This review presents a description of the literature published focused on post-COVID headache. Additionally, we discuss potential mechanisms and considerations for treatment of post-COVID headache. RECENT FINDINGS: Headache is one of the most common symptoms of COVID. Common characteristics are revealed when reviewing the phenotypes of headaches that have been described in patients with COVID-19, with most headache phenotypes resembling migraine and new persistent daily headache. Post-COVID headaches are often described as moderate to severe, persistent, and treatment refractory. This review highlights the diversity of presentation of headaches that present as a complication of COVID-19. Treatment of post-COVID headache is challenging, especially in the setting of a pandemic where resources are limited. CLINICAL CASE: A 42-year-old woman with a history of episodic migraine without aura presents over video visit with a new headache type. Her typical headaches are predominantly left sided, throbbing in nature, and associated with photophobia and phonophobia. They are fully relieved by oral sumatriptan 2 h after treatment. She describes this new headache as a constant, pulsating, holocephalic pain with no other migrainous features that have been ongoing for 6 weeks. She notes that the headache has been persistent since that time. She has tried over-the-counter acetaminophen and ibuprofen and her typical migraine abortive therapy without relief. She is debilitated and wonders if there is anything that will take the pain away. She shares that she tested positive for COVID-19 about 2 days prior to headache onset and has associated rhinorrhea, anosmia, and ageusia.

Targeting SARS-CoV-2: a systematic drug repurposing approach to identify promising inhibitors against 3C-like proteinase and 2'-O-ribose methyltransferase.

The recent pandemic associated with SARS-CoV-2, a virus of the Coronaviridae family, has resulted in an unprecedented number of infected people. The highly contagious nature of this virus makes it imperative for us to identify promising inhibitors from pre-existing antiviral drugs. Two druggable targets, namely 3C-like proteinase (3CLpro) and 2'-O-ribose methyltransferase (2'-O-MTase) were selected in this study due to their indispensable nature in the viral life cycle. 3CLpro is a cysteine protease responsible for the proteolysis of replicase polyproteins resulting in the formation of various functional proteins, whereas 2'-O-MTase methylates the ribose 2'-O position of the first and second nucleotide of viral mRNA, which sequesters it from the host immune system. The selected drug target proteins were screened against an in-house library of 123 antiviral drugs. Two promising drug molecules were identified for each protein based on their estimated free energy of binding (ΔG), the orientation of drug molecules in the active site and the interacting residues. The selected protein-drug complexes were then subjected to MD simulation, which consists of various structural parameters to equivalently reflect their physiological state. From the virtual screening results, two drug molecules were selected for each drug target protein [Paritaprevir (ΔG = -9.8 kcal/mol) & Raltegravir (ΔG = -7.8 kcal/mol) for 3CLpro and Dolutegravir (ΔG = -9.4 kcal/mol) and Bictegravir (ΔG = -8.4 kcal/mol) for 2'-OMTase]. After the extensive computational analysis, we proposed that Raltegravir, Paritaprevir, Bictegravir and Dolutegravir are excellent lead candidates for these crucial proteins and they could become potential therapeutic drugs against SARS-CoV-2. Communicated by Ramaswamy H. Sarma.

Physician Perspective and Key Satisfaction Indicators with Rapid Telehealth Adoption During the Coronavirus Disease 2019 Pandemic.

Background: Physician satisfaction with telehealth during the coronavirus disease 2019 pandemic is a strong indicator for future use. Validated surveys can guide improvement and future expansion of telehealth programs. Introduction: This study examines physician and advanced practice provider perspectives and satisfaction using telehealth at UPMC Pinnacle and to assess key predictors of future use in ambulatory care. Methods: A web-based Likert scale survey of UPMC Pinnacle physicians and advanced practice providers was conducted in May-June 2020. Cronbach's alpha was used to measure the survey's internal consistency. Crosstab analysis and multivariate regression were used to analyze the interrelationships between variables. Results: A significant majority (64%) of physicians responded positively that they enjoyed telehealth video visits. A majority (65%) felt that the physician-patient relationship was unimpaired during telehealth visits, but only 29% of the respondents felt they were able to examine the patients properly. Providers who experienced good video and audio quality were 3.68 times more likely to enjoy telehealth visits (p < 0.001, 95% confidence interval 2.05-6.61) than those with less-than-optimal video and audio quality. Logistic regression shows a strong correlation between the audio and image quality and respondents' satisfaction with telehealth. Discussion: The key barriers for patients when using telehealth are perceived to be the ability to use a smartphone app, password management, or video/microphone features. For clinicians, barriers include problems with seeing and hearing on the platform. Conclusions: Patient education and improvement of audio and image quality are essential for improving telehealth usage and satisfaction.

Ten Eleven Things Not to Say to Healthcare Professionals During the Coronavirus Disease 2019 Pandemic.

On March 11, 2020, the infection caused by the coronavirus disease 2019 (COVID-19) virus was declared a pandemic. Throughout this pandemic, healthcare professionals (HCPs) have experienced difficulties stemming from poor communications, resource scarcity, lack of transparency, disbelief, and threats to the safety of their loved ones, their patients, and themselves. As part of these hardships, negative statements have been heard repeatedly. This paper describes 11 scenarios of unhelpful and dysfunctional messages heard by the authors and their colleagues during the COVID-19 pandemic, reported to us by a combination of peers, administrative leadership, and the public. We explain why not to use such messaging, and we suggest more helpful and compassionate expressions based upon recommendations published by scientific organizations and well-established psychological principles. The first 10 scenarios discussed include (1) lack of understanding regarding the extent of the pandemic; (2) shaming over not seeing patients in person; (3) lack of clear and consistent communication from leadership on pandemic-related practice changes; (4) opinions that personal protective equipment (PPE) use by HCPs causes fear or is unnecessary; (5) forcing in-person care without appropriate PPE; (6) the risk of exposure to asymptomatic individuals as it relates to opening clinics; (7) media gag orders; (8) pay and benefit reductions; (9) spreading of misinformation about the COVID-19 pandemic; and (10) workload expectations. The 11th scenario addresses HCPs' psychological and physical reactions to this challenging and prolonged stressful situation. We close by discussing the need for support and compassion at this difficult and unpredictable time and by offering suggestions to foster resilience and feelings of self-efficacy among HCPs.

A comprehensive review on promising anti-viral therapeutic candidates identified against main protease from SARS-CoV-2 through various computational methods.

BACKGROUND: The COVID-19 pandemic caused by SARS-CoV-2 has shown an exponential trend of infected people across the planet. Crediting its virulent nature, it becomes imperative to identify potential therapeutic agents against the deadly virus. The 3-chymotrypsin-like protease (3CLpro) is a cysteine protease which causes the proteolysis of the replicase polyproteins to generate functional proteins, which is a crucial step for viral replication and infection. Computational methods have been applied in recent studies to identify promising inhibitors against 3CLpro to inhibit the viral activity. This review provides an overview of promising drug/lead candidates identified so far against 3CLpro through various in silico approaches such as structure-based virtual screening (SBVS), ligand-based virtual screening (LBVS) and drug-repurposing/drug-reprofiling/drug-retasking. Further, the drugs have been classified according to their chemical structures or biological activity into flavonoids, peptides, terpenes, quinolines, nucleoside and nucleotide analogues, protease inhibitors, phenalene and antibiotic derivatives. These are then individually discussed based on the various structural parameters namely estimated free energy of binding (ΔG), key interacting residues, types of intermolecular interactions and structural stability of 3CLpro-ligand complexes obtained from the results of molecular dynamics (MD) simulations. CONCLUSION: The review provides comprehensive information of potential inhibitors identified through several computational methods thus far against 3CLpro from SARS-CoV-2 and provides a better understanding of their interaction patterns and dynamic states of free and ligand-bound 3CLpro structures.

Identification of promising antiviral drug candidates against non-structural protein 15 (NSP15) from SARS-CoV-2: an in silico assisted drug-repurposing study.

The recent COVID-19 pandemic caused by SARS-CoV-2 has recorded a high number of infected people across the globe. The virulent nature of the virus makes it necessary for us to identify promising therapeutic agents in a time-sensitive manner. The current study utilises an in silico based drug repurposing approach to identify potential anti-viral drug candidates targeting non-structural protein 15 (NSP15), i.e. a uridylate specific endoribonuclease of SARS-CoV-2 which plays an indispensable role in RNA processing and viral immune evasion from the host immune system. The NSP15 protein was screened against an in-house library of 123 antiviral drugs obtained from the DrugBank database from which three promising drug candidates were identified based on their estimated binding affinities (ΔG), estimated inhibition constants (Ki), the orientation of drug molecules in the active site and the key interacting residues of NSP15. Molecular dynamics (MD) simulations were performed for the screened drug candidates in complex with NSP15 as well as the apo form of NSP15 to mimic their physiological states. Based on the stable MD simulation trajectories, the binding free energies of the screened NSP15-drug complexes were calculated using the MM/PBSA approach. Two candidate drugs, Simeprevir and Paritaprevir, achieved the lowest binding free energies for NSP15, with a value of -259.522 ± 17.579 and -154.051 ± 33.628 kJ/mol, respectively. In addition, their complexes with NSP15 also exhibited the strongest structural stabilities. Taken together, we propose that Simeprevir and Paritaprevir are promising drug candidates to inhibit NSP15 and may act as potential therapeutic agents against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

COVID-19 and Headache Medicine: A Narrative Review of Non-Steroidal Anti-Inflammatory Drug (NSAID) and Corticosteroid Use.

OBJECTIVE: To summarize the current literature on non-steroidal anti-inflammatory drug and corticosteroid use during the coronavirus disease 2019 (COVID-19) pandemic, recognizing that these are commonly used treatments in the field of headache medicine. BACKGROUND: The use of non-steroidal anti-inflammatory drugs and corticosteroids in patients during the COVID-19 pandemic has been a controversial topic within the medical community and international and national health organizations. Lay press and social media outlets have circulated opinions on this topic despite the fact that the evidence for or against the use of these medications is sparse. In the field of headache medicine, these medications are used commonly and both patients and clinicians may have questions or hesitations pertaining to their use during the COVID-19 pandemic. METHODS: A detailed search of the scientific and popular literature was performed. RESULTS: There is limited literature pertaining to the safety of non-steroidal anti-inflammatory drugs and corticosteroids during the COVID-19 pandemic. To date, there are no clear scientific data that preclude the use of non-steroidal anti-inflammatory drugs in the general population who may acquire COVID-19 or in those acutely infected with the virus. Several health organizations have concluded that treatment with corticosteroids during active infection should be avoided due to concerns of prolonged viral shedding in the respiratory tract and the lack of survival benefit based on the data from past coronaviruses and influenza virus; specific exceptions exist including treatment for underlying asthma or chronic obstructive pulmonary disease, septic shock, and acute respiratory distress syndrome. CONCLUSION: Scientific information regarding the COVID-19 pandemic is constantly evolving, and limited or contradictory information can lead to confusion for both patients and clinicians. It is recommended that prior to prescribing non-steroidal anti-inflammatory drugs and steroids for the treatment of headache, clinicians have open discussions with their patients about the potential risks and benefits of using these medications during the COVID-19 pandemic. This manuscript summarizes the currently available evidence and understanding about these risks and benefits to help clinicians navigate such discussions.

Migraine Care in the Era of COVID-19: Clinical Pearls and Plea to Insurers.

OBJECTIVE: To outline strategies for the treatment of migraine which do not require in-person visits to clinic or the emergency department, and to describe ways that health insurance companies can remove barriers to quality care for migraine. BACKGROUND: COVID-19 is a global pandemic causing widespread infections and death. To control the spread of infection we are called to observe "social distancing" and we have been asked to postpone any procedures which are not essential. Since procedural therapies are a mainstay of headache care, the inability to do procedures could negatively affect our patients with migraine. In this manuscript we review alternative therapies, with particular attention to those which may be contra-indicated in the setting of COVID-19 infection. DESIGN/RESULTS: The manuscript reviews the use of telemedicine visits and acute, bridge, and preventive therapies for migraine. We focus on evidence-based treatment where possible, but also describe "real world" strategies which may be tried. In each section we call out areas where changes to rules from commercial health insurance companies would facilitate better migraine care. CONCLUSIONS: Our common goal as health care providers is to maximize the health and safety of our patients. Successful management of migraine with avoidance of in-person clinic and emergency department visits further benefits the current urgent societal goal of maintaining social distance to contain the COVID-19 pandemic.