Computational analysis of human host binding partners of chikungunya and dengue viruses during coinfection

2021 ◽  
Vol 79 (8) ◽  
Author(s):  
Ritu Ghildiyal ◽  
Reema Gabrani
Keyword(s):  
Clinical Manifestations ◽  
Host Protein ◽  
Severe Illness ◽  
P53 Signaling ◽  
Clinical Complications ◽  
Binding Partners ◽  
Viral Interactions ◽  
Human Proteins ◽  
Approved Drugs ◽  
Regulation Of Cell Cycle

ABSTRACT Mosquito-borne viral diseases like chikungunya and dengue infections can cause severe illness and have become major public health concerns. Chikungunya virus (CHIKV) and dengue virus (DENV) infections share similar primary clinical manifestations and are transmitted by the same vector. Thus, the probability of their coinfection gets increased with more severe clinical complications in the patients. The present study was undertaken to elucidate the common human interacting partners of CHIKV and DENV proteins during coinfection. The viral–host protein–protein interactome was constructed using Cytoscape. Subsequently, significant host interactors were identified during coinfection. The network analysis elucidated 57 human proteins interacting with both CHIKV and DENV, represented as hub-bottlenecks. The functional and biological analyses of the 40 hub-bottlenecks revealed that they are associated with phosphoinositide 3-kinases (PI3K)/AKT, p53 signaling pathways, regulation of cell cycle and apoptosis during coinfection. Moreover, the molecular docking analysis uncovered the tight and robust binding of selected hub-bottlenecks with CHIKV/DENV proteins. Additionally, 23 hub-bottlenecks were predicted as druggable candidates that could be targeted to eradicate the host–viral interactions. The elucidated common host binding partners during DENV and CHIKV coinfection as well as indicated approved drugs can support the therapeutics development.

scholarly journals Innate and Adaptive Immunity Imbalance With Severe COVID-19 Pneumonia in Children and Adults

2021 ◽  
Vol 9 ◽  
Author(s):  
Zahra Shokati Eshkiki ◽  
Arman Shahriari ◽  
Maryam Seyedtabib ◽  
Mehdi Torabizadeh ◽  
Mohammad Ali Assarehzadegan ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Clinical Symptoms ◽  
Clinical Manifestations ◽  
Chest Ct ◽  
Adult Patients ◽  
Severe Illness ◽  
Clinical Complications ◽  
Immune Alterations

Introduction: Little is known about the laboratory and radiological characteristics and clinical significance of peripheral immune alterations in patients with coronavirus disease 2019 (COVID-19). This study aims to clarify these aspects in children and adults with COVID-19.Methods: In this consecutive pilot study, COVID-19 patients with the confirmed pneumonia and real-time RT-PCR were recruited prospectively in June 2020. The clinical, chest CT, and laboratory features, such as lymphocyte subpopulations, were analyzed for each individual.Results: Forty confirmed COVID-19 patients, 11 severe children, 12 severe adults, and 17 critical adult patients, besides 20 healthy pediatrics and 14 healthy adults as controls, were enrolled prospectively. Adult patients, especially critical ones, had a much higher prevalence of laboratory and chest CT abnormalities. Data regarding immune cell subsets in children patients, compared with matched controls, had higher CD3+ CD8+ T cells (p = 0.004) and lower CD4+/CD8+ ratio (p = 0.042), while adult patients, compared with matched controls, had lower CD14+ monocytes (p = 0.032). Adult patients were also categorized as experiencing critical or severe illness on admission and, compared with severe patients, had lower total lymphocytes (p < 0.047), CD3+ T-lymphocytes (p < 0.002), and CD3+ CD8+ T cells (p = 0.001) and, on the other hand, had higher CD3+ CD4+ T cells (p = 0.012) and CD4+/CD8+ ratio (p = 0.003). Non survived adults, compared with survived patients, had significantly lower CD3+ T-lymphocyte (p = 0.005).Conclusion: Unlike adult patients, who compared with matched controls and had more comorbidities, higher frequency of severe clinical symptoms, laboratory abnormalities, and immune cells alteration, clinical manifestations of COVID-19 in children (compared with matched controls) were relatively mild, and fewer clinical complications were seen either, perhaps because of a milder inflammatory response following their peripheral innate and adaptive immune cell alteration pattern.

scholarly journals Prediction of severe adverse events, modes of action and drug treatments for COVID-19’s complications

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Courtney Astore ◽  
Hongyi Zhou ◽  
Joshy Jacob ◽  
Jeffrey Skolnick
Keyword(s):  
Adverse Events ◽  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Molecular Features ◽  
Disease Protein ◽  
Human Proteins ◽  
Drug Treatments ◽  
Severe Adverse Events ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractFollowing SARS-CoV-2 infection, some COVID-19 patients experience severe host driven adverse events. To treat these complications, their underlying etiology and drug treatments must be identified. Thus, a novel AI methodology MOATAI-VIR, which predicts disease-protein-pathway relationships and repurposed FDA-approved drugs to treat COVID-19’s clinical manifestations was developed. SARS-CoV-2 interacting human proteins and GWAS identified respiratory failure genes provide the input from which the mode-of-action (MOA) proteins/pathways of the resulting disease comorbidities are predicted. These comorbidities are then mapped to their clinical manifestations. To assess each manifestation’s molecular basis, their prioritized shared proteins were subject to global pathway analysis. Next, the molecular features associated with hallmark COVID-19 phenotypes, e.g. unusual neurological symptoms, cytokine storms, and blood clots were explored. In practice, 24/26 of the major clinical manifestations are successfully predicted. Three major uncharacterized manifestation categories including neoplasms are also found. The prevalence of neoplasms suggests that SARS-CoV-2 might be an oncovirus due to shared molecular mechanisms between oncogenesis and viral replication. Then, repurposed FDA-approved drugs that might treat COVID-19’s clinical manifestations are predicted by virtual ligand screening of the most frequent comorbid protein targets. These drugs might help treat both COVID-19’s severe adverse events and lesser ones such as loss of taste/smell.

Prognostic implication of hypocalcaemia in COVID-19: a systematic review

2021 ◽  
Vol 22 (2) ◽  
pp. 124-132
Author(s):  
T.A. Azeez ◽  
S. Lakoh ◽  
O.T. Bamidele ◽  
E. Ekhaiyeme ◽  
S.A. Nwosu
Keyword(s):  
Systematic Review ◽  
Prognostic Factors ◽  
Prognostic Factor ◽  
Clinical Manifestations ◽  
Severe Illness ◽  
Prognostic Implication ◽  
Poor Prognostic Factor ◽  
Medical Databases ◽  
Reactive Protein ◽  
Prognostic Implications

Coronavirus disease-2019 (COVID-19) has been declared as a pandemic affecting several millions of people worldwide. It has varied clinical manifestations ranging from asymptomatic to critical illness. It has led to the mortality of several affected individuals. However, the prognosis seems to vary from one person to the other and efforts are being made to identify the prognostic factors. Hypocalcaemia has been identified as a poor prognostic factor with a high frequency among individuals affected with COVID-19. This review aims to estimate the prevalence of hypocalcaemia among COVID-19 patients and identify the poor prognostic factors associated with the presence of hypocalcaemia in COVID-19 patients. Electronic medical databases were searched for publications on the prognostic implications of hypocalcaemia in COVID-19 infection, and relevant articles were selected for systematic review following PRISMA algorithm. The prevalence of hypocalcaemia among patients with COVID-19 was 40.0-74.4%. There was a significant association between the rate of hospital admission, intensive care unit (ICU) admission as well as septic shock and hypocalcaemia in patients with COVID-19. Hypocalcaemia is also associated with a higher mortality rate in these patients. COVID-19 patients with hypocalcaemia tend to have elevated C-reactive protein, interleukin6, alanine transaminase, procalcitonin, serum creatinine and low albumin.   Hypocalcaemia is common in COVID-19 patients and is a poor prognostic factor in these patients. Presence of hypocalcaemia is  associated with a severe illness and even death. Keywords: COVID-19; hypocalcaemia; prognosis; systematic review

scholarly journals Pathogenesis, clinical manifestations and complications of coronavirus disease 2019 (COVID-19)

2020 ◽  
Vol 15 (13) ◽  
pp. 1287-1305
Author(s):  
Elaheh Kordzadeh-Kermani ◽  
Hossein Khalili ◽  
Iman Karimzadeh
Keyword(s):  
Respiratory System ◽  
Literature Search ◽  
Clinical Manifestations ◽  
Google Scholar ◽  
Nervous Systems ◽  
Clinical Complications ◽  
Central Nervous Systems ◽  
Degrees Of Severity

Aim: Despite the similarities in the pathogenesis of the beta coronaviruses, the precise infective mechanisms of SARS-CoV-2 remain unclear. Objective: In this review, we aim to focus on the proposed theories behind the pathogenesis of SARS-CoV-2 and highlight the clinical complications related to COVID-19. Methods: We conducted a literature search in Pubmed, Scopus and Google Scholar for the relevant articles regarding clinical complications and pathogenesis of COVID-19. Results: Related articles were included and discussed. Conclusion: Respiratory system and the lungs are the most commonly involved sites of COVID-19 infection. Cardiovascular, liver, kidneys, gastrointestinal and central nervous systems are involved with different frequencies and degrees of severity.

scholarly journals Evidence of a wide gap between COVID-19 in humans and animal models: a systematic review

Critical Care ◽  
2020 ◽  
Vol 24 (1) ◽  
Author(s):  
Salleh N. Ehaideb ◽  
Mashan L. Abdullah ◽  
Bisher Abuyassin ◽  
Abderrezak Bouchama
Keyword(s):  
Animal Models ◽  
Nonhuman Primates ◽  
Clinical Manifestations ◽  
Full Recovery ◽  
Severe Illness ◽  
Original Research ◽  
Lung Pathology ◽  
Inclusion Criteria ◽  
Hypoxemic Respiratory Failure ◽  
Wide Gap

Abstract Background Animal models of COVID-19 have been rapidly reported after the start of the pandemic. We aimed to assess whether the newly created models reproduce the full spectrum of human COVID-19. Methods We searched the MEDLINE, as well as BioRxiv and MedRxiv preprint servers for original research published in English from January 1 to May 20, 2020. We used the search terms (COVID-19) OR (SARS-CoV-2) AND (animal models), (hamsters), (nonhuman primates), (macaques), (rodent), (mice), (rats), (ferrets), (rabbits), (cats), and (dogs). Inclusion criteria were the establishment of animal models of COVID-19 as an endpoint. Other inclusion criteria were assessment of prophylaxis, therapies, or vaccines, using animal models of COVID-19. Result Thirteen peer-reviewed studies and 14 preprints met the inclusion criteria. The animals used were nonhuman primates (n = 13), mice (n = 7), ferrets (n = 4), hamsters (n = 4), and cats (n = 1). All animals supported high viral replication in the upper and lower respiratory tract associated with mild clinical manifestations, lung pathology, and full recovery. Older animals displayed relatively more severe illness than the younger ones. No animal models developed hypoxemic respiratory failure, multiple organ dysfunction, culminating in death. All species elicited a specific IgG antibodies response to the spike proteins, which were protective against a second exposure. Transient systemic inflammation was observed occasionally in nonhuman primates, hamsters, and mice. Notably, none of the animals unveiled a cytokine storm or coagulopathy. Conclusions Most of the animal models of COVID-19 recapitulated mild pattern of human COVID-19 with full recovery phenotype. No severe illness associated with mortality was observed, suggesting a wide gap between COVID-19 in humans and animal models.

Human Herpes Virus-6 and Clinical Manifestations After Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1960-1960
Author(s):  
Raffaella Greco ◽  
Francesca Lorentino ◽  
Daniela Clerici ◽  
Francesca Matteazzi ◽  
Alessandra Forcina ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cerebrospinal Fluid ◽  
Stem Cell ◽  
Viral Load ◽  
Hematopoietic Stem Cell Transplantation ◽  
Clinical Manifestations ◽  
Median Viral Load ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Clinical Complications

Abstract Abstract 1960 BACKGROUND: Human herpesvirus 6 (HHV-6) is increasingly recognized as an opportunistic and potentially life-threatening pathogen in recipients of allogeneic Hematopoietic Stem Cell Transplantation (HSCT). Reported clinical manifestations of HHV-6 infection in transplanted patients are skin rash, interstitial pneumonia, bone marrow suppression and encephalitis. Moreover, an increasing number of clinical reports suggest that HHV-6 can facilitate the occurrence of other severe clinical complications of allogeneic HSCT, including Graft-versus-Host Disease (GvHD), ultimately increasining transplant-related mortality. Still, the actual incidence of HHV-6 infection in recipients of HSCT and the causative link between infection and clinical complications remain elusive, mostly due to the small and heterogeneous patient cohorts analyzed to date. METHODS: From January 2009 to July 2011, we retrospectively evaluated 43 consecutive adult patients (median age 51 years) who developed positivity to HHV-6 after allogeneic HSCT for high-risk hematological malignancies. Stem cell donor was for 30 patients family haploidentical, for 5 an HLA identical sibling, and for 8 an unrelated volunteer (1 of which cord blood). The viral load was determined by quantitative PCR in cell-free body fluids such as plasma, bronchoalveolar lavage, cerebrospinal fluid, bone marrow aspirates or in gastrointestinal biopsies. At the time of positivity all patients were receiving acyclovir as viral prophylaxis except 5. Sixteen patients had clinical acute GvHD at time of HHV-6 positivity (grade III-IV in 14), and 33 were profoundly immunosuppressed with variable association of 2–4 immunosuppressive drugs (steroids included). Moreover concomitant CMV positivity was detected in 11 patients, while a severe neutropenia in 12. RESULTS: Median time from allogeneic HSCT to HHV-6 reactivation was 36 days (range: 7–625). In 19 patients HHV-6 was detected in plasma, with a median viral load of 19,454 cp/mL (34-4,524,600); 15 had concomitant fever, 5 skin rash of new onset, 4 impaired liver function, and 5 developed cytopenia subsequently to the infection. In 7 patients HHV-6 was detected in the bone marrow: the median viral load was 163'800 cp/mL (568-1'552'982). In 8 patients, all febrile, HHV-6 was observed in bronchoalveolar lavage samples with a median of 4'149 cp/mL (85–39250). In 16 patients, 10 with documented gut aGvHD, 11 with diarrhoea, HHV-6 was detected in gastrointestinal biopsies with a median of 7'510 cp/mL (120-4'524'600). HHV-6 was found in cerebrospinal fluid in 4 cases (all within 30 days after HSCT); the median viral load was 29'352 cp/mL (4'508-1'552'982); all these patients experienced encephalitis with confusion and anxiety, 2 suffered seizures and 3 showed abnormal findings on brain MRI. Amongst patients with organ localizations of HHV-6 only 28% had concomitant plasma positivity. HHV-6 positivity led to antiviral pharmacological treatment only when associated with clinical manifestations (n=21), using as first choice therapy foscarnet. Amongst the total 43 patients with documented HHV-6 positivity 11 completely solved the clinical event, whereas 19 (44%) died. CONCLUSIONS: HHV-6 infection/reactivation is associated with high morbidity and mortality in patients who undergo allogeneic HSCT. HHV-6 infection typically occurred close to the time of neutrophil engraftment. HSCT from an HLA-mismatched donor and steroid administration were associated with increased risk of active HHV-6 infection. Development of encephalitis was associated with high HHV-6 viral load. The regular monitoring of HHV-6 DNA in allogeneic HSCT recipients, using a real-time PCR assay, may be useful for identifying active HHV-6 infection and for the introduction of a pre-emptive treatment, possibly reducing the incidence of the most severe clinical complications. Disclosures: No relevant conflicts of interest to declare.

Human Herpes Virus 6 Infection in 54 Patients after Allogeneic Hematopoietic Stem Cell Transplantation: Clinical Manifestations and Outcome

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3899-3899
Author(s):  
Raffaella Greco ◽  
Lara Crucitti ◽  
Sara Racca ◽  
Roee Dvir ◽  
Francesca Lorentino ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Gvhd ◽  
Clinical Manifestations ◽  
Rank Test ◽  
P Value ◽  
Hematopoietic Stem ◽  
Clinical Complications ◽  
Log Rank Test ◽  
Blue Line

Abstract BACKGROUND: Human herpesvirus type 6 (HHV-6) is increasingly recognized as an opportunistic and potentially life-threatening pathogen in recipients of allogeneic hematopoietic stem cell transplantation (AlloSCT). HHV-6 is a member of the beta herpesvirus subfamily (genus Roseolovirus). HHV-6 infection is recognized as the cause of a febrile disease and exanthem subitum in early childhood. Approximately 60% of solid organ transplant and 40% of patients after alloSCT experienced HHV-6 reactivation. Reported clinical manifestations of HHV-6 infection in transplanted patients are skin rash, interstitial pneumonia, bone marrow suppression and encephalitis. Moreover, some clinical reports suggest that HHV-6 can facilitate the occurrence of severe clinical complications of alloSCT, increasing transplant-related mortality. METHODS: From January 2009 to February 2013, we retrospectively evaluated 54 consecutive adult patients (median age 50 years) who developed positivity to HHV-6 after alloSCT for high-risk hematological malignancies. Stem cell donors were family haploidentical (37), HLA identical sibling (8), unrelated volunteer (6), cord blood (3). The viral load was determined by quantitative PCR (Nanogen Advanced Diagnostic S.r.L) in cell-free body fluids such as plasma, bronchoalveolar lavage (BAL), cerebrospinal fluid (CSF), bone marrow (BM) aspirates or in gastrointestinal biopsies. RESULTS: Median time from alloSCT to HHV-6 reactivation was 34 days (range: 0-705). Thirty-one patients presented HHV-6 positive in plasma, 9/54 in BM, 33/54 in gut biopsies or BAL, 7/54 in CSF. At the time of viral positivity all pts were receiving acyclovir as viral prophylaxis except five. Twenty-nine patients had acute graft versus host disease (GvHD). Twenty-two out of these twenty-nine patients experienced a grade III-IV acute GvHD, requiring high dose steroids in twenty-six cases. A concomitant CMV positivity was detected in 15/54 patients. The median absolute count of CD3+ lymphocytes was 207 cells/mcl. In 52/54 cases we reported HHV-6 clinical manifestations: fever (43), skin rash (22), hepatitis (19), diarrhoea (24), encephalitis (10), BM suppression (18), delayed engraftment (11). HHV-6 positivity led to antiviral pharmacological treatment in 37/54 cases, using as first choice therapy foscarnet. Amongst the total fifty-four patients with documented HHV-6 positivity thirty-one solved the clinical event. However the mortality rate was relatively high in this population (overall survival (OS) ±SE at 1 year after HHV-6 reactivation was 38% ± 7%), mainly related to severe infections or GvHD. A better OS is significantly associated with CD3+ cells ≥200/mcl at the time of HHV-6 reactivation (fig 1) (OS at 1 year 63% compared to 11% for patients with CD3 <200/mcl; HR: 0.27, 95% CI 0.12-0.54, p=0.0002). The overall survival of these patients was also positively affected by the absence of acute GvHD grade III-IV at time of viral reactivation (HR: 0.03, 95% CI 1.08-4.03, p=0.03) and by the complete disease remission at time of HSCT (HR:0.26, 95% CI 0.07-0.89, p=0.03). In this analysis the overall survival was not significantly influenced by steroids administration (HR: 1.36, 95% CI 0.71-2.60, p=0.36), time after alloSCT (HR: 1.30, 95% CI 0.51-3.33, p=0.59), type of antiviral prophylaxis (HR: 1.02, 95% CI 0.45-2.33, p=0.96), plasma viral load (HR:1.18, 95% CI 0.51-2.76, p=0.69) and organ involvement (HR:1.14, 95% CI 0.59-2.20, p=0.70). CONCLUSIONS: This retrospective study confirms a correlation of HHV-6 with high morbidity and mortality rates after alloSCT, thus suggesting a regular HHV-6 monitoring in alloSCT recipients. The regular monitoring of HHV-6 DNA, using a real-time PCR assay, may be useful for identifying active HHV-6 infection and for the introduction of a pre-emptive treatment, possibly reducing the incidence of the most severe clinical complications. Despite HHV-6 detection typically occurred early after alloSCT, a better immune reconstitution has the potential to improve clinical outcome. Figure 1: Overall survival after alloSCT in HHV-6 positive patients: green line showed patients with more than 200/mcl CD3+ cells, blue line the ones with less than 200/mcl CD3+ cells at HHV-6 reactivation. P value is provided by Log Rank test. Figure 1:. Overall survival after alloSCT in HHV-6 positive patients: green line showed patients with more than 200/mcl CD3+ cells, blue line the ones with less than 200/mcl CD3+ cells at HHV-6 reactivation. P value is provided by Log Rank test. Disclosures Bonini: MolMed S.p.A.: Consultancy.

scholarly journals ACUTE KIDNEY INJURY CAUSED BY Crotalus AND Bothrops SNAKE VENOM: A REVIEW OF EPIDEMIOLOGY, CLINICAL MANIFESTATIONS AND TREATMENT

2013 ◽  
Vol 55 (5) ◽  
pp. 295-301 ◽  
Author(s):  
Polianna L.M.M. Albuquerque ◽  
Camilla N. Jacinto ◽  
Geraldo B. Silva Junior ◽  
Juliana B. Lima ◽  
Maria do Socorro B. Veras ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Snake Venom ◽  
Rural Areas ◽  
Renal Involvement ◽  
Clinical Manifestations ◽  
Kidney Injury ◽  
Public Health Problem ◽  
Important Public Health Problem ◽  
Young Males ◽  
Clinical Complications

SUMMARY Ophidic accidents are an important public health problem due to their incidence, morbidity and mortality. An increasing number of cases have been registered in Brazil in the last few years. Several studies point to the importance of knowing the clinical complications and adequate approach in these accidents. However, knowledge about the risk factors is not enough and there are an increasing number of deaths due to these accidents in Brazil. In this context, acute kidney injury (AKI) appears as one of the main causes of death and consequences for these victims, which are mainly young males working in rural areas. Snakes of the Bothrops and Crotalus genera are the main responsible for renal involvement in ophidic accidents in South America. The present study is a literature review of AKI caused by Bothrops and Crotalus snake venom regarding diverse characteristics, emphasizing the most appropriate therapeutic approach for these cases. Recent studies have been carried out searching for complementary therapies for the treatment of ophidic accidents, including the use of lipoic acid, simvastatin and allopurinol. Some plants, such as Apocynaceae, Lamiaceae and Rubiaceae seem to have a beneficial role in the treatment of this type of envenomation. Future studies will certainly find new therapeutic measures for ophidic accidents.

scholarly journals MOATAI-VIR - an AI algorithm that predicts severe adverse events and molecular features for COVID-19’s complications

2021 ◽  
Author(s):  
Courtney Astore ◽  
Hongyi Zhou ◽  
Joshy Jacob ◽  
Jeffrey Skolnick
Keyword(s):  
Adverse Events ◽  
Molecular Mechanisms ◽  
Chromosomal Abnormalities ◽  
Clinical Manifestations ◽  
Host Responses ◽  
Molecular Features ◽  
Disease Protein ◽  
Human Proteins ◽  
Severe Adverse Events ◽  
Patients Experience

AbstractFollowing SARS-CoV-2 infection, some COVID-19 patients experience severe adverse events caused by pathogenic host responses. To treat these complications, their underlying etiology must be identified. Thus, a novel AI-based methodology, MOATAI-VIR, which predicts disease-protein-pathway relationships for 22 clinical manifestations attributed to COVID-19 was developed. SARS-CoV-2 interacting human proteins and GWAS identified respiratory failure associated risk genes provide the input from which the mode-of-action (MOA) proteins/pathways of the resulting disease comorbidities are predicted. These comorbidities are then mapped to their clinical manifestations. Three uncharacterized manifestation categories are found: neoplasms, mental and behavioral disorders, and congenital malformations, deformations, and chromosomal abnormalities. The prevalence of neoplasms suggests a possible association between COVID-19 and cancer, whether by shared molecular mechanisms between oncogenesis and viral replication, or perhaps, SARS-CoV-2 is an oncovirus. To assess the molecular basis of each manifestation, the proteins shared across each group of comorbidities were prioritized and subject to global pathway analysis. From these most frequent pathways, the molecular features associated with hallmark COVID-19 phenotypes, such as loss of sense of smell/taste, unusual neurological symptoms, cytokine storm, and blood clots were explored. Results of MOATAI-VIR are available for academic users at: http://pwp.gatech.edu/cssb/MOATAI-VIR/.

scholarly journals Identification of Influenza PAN Endonuclease Inhibitors via 3D-QSAR Modeling and Docking-Based Virtual Screening

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7129
Author(s):  
Chao Zhang ◽  
Junjie Xiang ◽  
Qian Xie ◽  
Jing Zhao ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Influenza A ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Docking Studies ◽  
Toxicity Assessment ◽  
Host Protein ◽  
Qsar Modeling ◽  
Discovery Studio ◽  
Clinical Drugs ◽  
Approved Drugs

Structural and biochemical studies elucidate that PAN may contribute to the host protein shutdown observed during influenza A infection. Thus, inhibition of the endonuclease activity of viral RdRP is an attractive approach for novel antiviral therapy. In order to envisage structurally diverse novel compounds with better efficacy as PAN endonuclease inhibitors, a ligand-based-pharmacophore model was developed using 3D-QSAR pharmacophore generation (HypoGen algorithm) methodology in Discovery Studio. As the training set, 25 compounds were taken to generate a significant pharmacophore model. The selected pharmacophore Hypo1 was further validated by 12 compounds in the test set and was used as a query model for further screening of 1916 compounds containing 71 HIV-1 integrase inhibitors, 37 antibacterial inhibitors, 131 antiviral inhibitors and other 1677 approved drugs by the FDA. Then, six compounds (Hit01–Hit06) with estimated activity values less than 10 μM were subjected to ADMET study and toxicity assessment. Only one potential inhibitory ‘hit’ molecule (Hit01, raltegravir’s derivative) was further scrutinized by molecular docking analysis on the active site of PAN endonuclease (PDB ID: 6E6W). Hit01 was utilized for designing novel potential PAN endonuclease inhibitors through lead optimization, and then compounds were screened by pharmacophore Hypo1 and docking studies. Six raltegravir’s derivatives with significant estimated activity values and docking scores were obtained. Further, these results certainly do not confirm or indicate the seven compounds (Hit01, Hit07, Hit08, Hit09, Hit10, Hit11 and Hit12) have antiviral activity, and extensive wet-laboratory experimentation is needed to transmute these compounds into clinical drugs.

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