scholarly journals Synthesis and Identification of Novel Potential Thiadiazole Based Molecules Containing 1,2,3-triazole Moiety Against COVID-19 Main Protease Through Structure-Guided Virtual Screening Approach

2021 ◽  
Vol 12 (6) ◽  
pp. 8258-8270
Keyword(s):  
Infectious Disease ◽  
Mass Spectrometry ◽  
Chemical Composition ◽  
Virtual Screening ◽  
Respiratory Tract Infections ◽  
Essential Role ◽  
Main Protease ◽  
Ft Ir ◽  
Tract Infections ◽  
Virtual Screening Approach

In the present study, 1-(5-Methyl-1-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-1H-1,2,3-triazol-4-yl) ethan-1-one 2 was used as predecessor molecule for synthesis of methyl 2-(1-(5-methyl-1-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-1H-1,2,3-triazol-4-yl) ethylidene) hydrazine-1-carbodithioate 3. The latter compound was utilized to synthesize two new 1,3,4-thiadiazole-1,2,3-triazole hybrids 6 and 7 via its reaction with the appropriate hydrazonoyl halide derivatives 4 and 5. All the newly prepared derivatives' chemical composition was inferred from microanalytical and spectral data (FT-IR, Mass spectrometry, 1H-NMR, and 13C-NMR). Coronavirus disease (COVID-19) is an infectious disease that can cause respiratory tract infections of humans and vertebrate animals. Herein, we reported a structure-aided in silico virtual screening to identify their antiviral activity against Coronavirus through inhibition of main coronavirus protease, which plays an essential role in propagating the disease. The newly synthesized compounds showed good docking scores to COVID-19 main protease.

scholarly journals Discovery of Species-unique Peptide Biomarkers of Bacterial Pathogens by Tandem Mass Spectrometry-based Proteotyping

2020 ◽  
Vol 19 (3) ◽  
pp. 518-528 ◽  
Author(s):  
Roger Karlsson ◽  
Annika Thorsell ◽  
Margarita Gomila ◽  
Francisco Salvà-Serra ◽  
Hedvig E. Jakobsson ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Infectious Diseases ◽  
Respiratory Tract ◽  
Respiratory Tract Infections ◽  
Clinical Laboratory ◽  
Bacterial Pathogens ◽  
Clinical Samples ◽  
Tandem Ms ◽  
Adequate Treatment ◽  
Tract Infections

Mass spectrometry (MS) and proteomics offer comprehensive characterization and identification of microorganisms and discovery of protein biomarkers that are applicable for diagnostics of infectious diseases. The use of biomarkers for diagnostics is widely applied in the clinic and the use of peptide biomarkers is increasingly being investigated for applications in the clinical laboratory. Respiratory-tract infections are a predominant cause for medical treatment, although, clinical assessments and standard clinical laboratory protocols are time-consuming and often inadequate for reliable diagnoses. Novel methods, preferably applied directly to clinical samples, excluding cultivation steps, are needed to improve diagnostics of infectious diseases, provide adequate treatment and reduce the use of antibiotics and associated development of antibiotic resistance. This study applied nano-liquid chromatography (LC) coupled with tandem MS, with a bioinformatics pipeline and an in-house database of curated high-quality reference genome sequences to identify species-unique peptides as potential biomarkers for four bacterial pathogens commonly found in respiratory tract infections (RTIs): Staphylococcus aureus; Moraxella catarrhalis; Haemophilus influenzae and Streptococcus pneumoniae. The species-unique peptides were initially identified in pure cultures of bacterial reference strains, reflecting the genomic variation in the four species and, furthermore, in clinical respiratory tract samples, without prior cultivation, elucidating proteins expressed in clinical conditions of infection. For each of the four bacterial pathogens, the peptide biomarker candidates most predominantly found in clinical samples, are presented. Data are available via ProteomeXchange with identifier PXD014522. As proof-of-principle, the most promising species-unique peptides were applied in targeted tandem MS-analyses of clinical samples and their relevance for identifications of the pathogens, i.e. proteotyping, was validated, thus demonstrating their potential as peptide biomarker candidates for diagnostics of infectious diseases.

scholarly journals MODERN METHODS OF ETIOLOGICAL DIAGNOSING OF ACUTE COMMUNITY-ACQUIRED LOWER RESPIRATORY TRACT INFECTIONS

2021 ◽  
Vol 29 (3) ◽  
pp. 58-65
Author(s):  
O. L. Bororova ◽  
◽  
Y. O. Dziublyk ◽  
V.A. Iachnyk
Keyword(s):  
Mass Spectrometry ◽  
Respiratory Tract ◽  
Lower Respiratory Tract ◽  
Respiratory Tract Infections ◽  
Diagnostic Methods ◽  
Molecular Diagnostic ◽  
Lower Respiratory Tract Infections ◽  
Etiological Diagnosis ◽  
Modern Methods ◽  
Tract Infections

MODERN METHODS OF ETIOLOGICAL DIAGNOSING OF ACUTE COMMUNITY-ACQUIRED LOWER RESPIRATORY TRACT INFECTIONS O. L. Bororova, Y. O. Dziublyk, V.A. Iachnyk Abstract The review presents the possibilities presented by various methods of etiological diagnostics used in pulmonology. The main method of diagnosing acute community-aquired lower respiratory tract infections is the microbiological approach which includes microscopy of patient’s material with Gram staining, cultures on nutrient media, isolation of culture, identification and determination of susceptibility of a microorganism to antibiotics. But unfortunately the etiologocal factor cannot be detected in about half of patients. Recently, the popularity of molecular methods of etiological diagnosis has grown. They are characterized by greater sensitivity to microbiological methods and allow to get results faster. Molecular diagnostic tests are divided into four categories depending on the mechanism based on them: immunoassay, hybridization methods, amplification and sequencing methods. Among the tests based on the principles of immunoassay, noteworthy are rapid tests, which are most consistent with the idea of an ideal diagnostic tool in the field of laboratory medicine. They are fast, simple, cheap, highly sensitive and highly specific. However, as the appearance of specific antibodies in the body takes some time, the results of tests based on immunoassay remain positive for several weeks after the delayed episode of acute community-acquired lower respiratory tract infection, so they have diagnostic value only in the presence of clinical manifestations of the disease. The genetic approach allows the detection of infectious agents in the early stages of the disease, when serological and immunological methods are ineffective. Tests based on nucleic acid amplification, including PCR, have also become increasingly common recently. These methods should be used for the diagnosis of atypical pathogens and respiratory viruses, because their cultivation in culture is difficult. Sequencing and mass spectrometry methods are being actively developed, but there are limitations that prevent their use in everyday clinical practice. So the combination of microbiological approach with molecular diagnostic methods is the most optimal for the identification of the causative agent of acute community-acquired lower respiratory tract infections and the use of targeted etiotropic treatment. Key words: acute community-acquired lower respiratory tract infections, etiological diagnosis, microbiological, serological, immunological, molecular genetic methods, ICA, PCR, sequencing, mass spectrometry. Ukr. Pulmonol. J. 2021;29(3):58–65

scholarly journals Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs

2020 ◽  
Vol 117 (44) ◽  
pp. 27381-27387 ◽  
Author(s):  
Zhe Li ◽  
Xin Li ◽  
Yi-You Huang ◽  
Yaoxing Wu ◽  
Runduo Liu ◽  
...  
Keyword(s):  
Free Energy ◽  
Virtual Screening ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Free Energy Perturbation ◽  
Therapeutic Effects ◽  
Screening Approach ◽  
Main Protease ◽  
Energy Perturbation ◽  
Virtual Screening Approach

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and thus repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. Here we report a virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (Mpro). The accurate FEP-ABFE predictions were based on the use of a restraint energy distribution (RED) function, making the practical FEP-ABFE−based virtual screening of the existing drug library possible. As a result, out of 25 drugs predicted, 15 were confirmed as potent inhibitors of SARS-CoV-2 Mpro. The most potent one is dipyridamole (inhibitory constant Ki= 0.04 µM) which has shown promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki= 0.36 µM) and chloroquine (Ki= 0.56 µM) were also found to potently inhibit SARS-CoV-2 Mpro. We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts.

scholarly journals The Causes of Acute Fever Requiring Hospitalization in Geriatric Patients: Comparison of Infectious and NoninfectiousEtiology

2010 ◽  
Vol 2010 ◽  
pp. 1-6 ◽  
Author(s):  
A. Atahan Cagatay ◽  
Fatih Tufan ◽  
Fehmi Hindilerden ◽  
Sibel Aydin ◽  
Omer Celal Elcioglu ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Urinary Tract ◽  
Infectious Diseases ◽  
Respiratory Tract Infections ◽  
Geriatric Patients ◽  
Soft Tissue Infections ◽  
Hematological Diseases ◽  
Atypical Presentations ◽  
Tract Infections ◽  
Underlying Diseases

Introduction. Infectious diseases may present with atypical presentations in the geriatric patients. While fever is an important finding of infections, it may also be a sign of noninfectious etiology.Methods. Geriatric patients who were hospitalized for acute fever in our infectious diseases unit were included. Acute fever was defined as presentation within the first week of fever above .Results. 185 patients were included (82 males and 103 females). Mean age was years. The cause of fever was an infectious disease in 135 and noninfectious disease in 32 and unknown in 18 of the patients. The most common infectious etiologies were respiratory tract infections (), urinary tract infections (), and skin and soft tissue infections (). Noninfectious causes of fever were rheumatic diseases (), solid tumors (), hematological diseases (), and vasculitis (). A noninfectious cause of fever was present in one patient with no underlying diseases and in 31 of 130 patients with underlying diseases.Conclusion. Geriatric patients with no underlying diseases generally had infectious causes of fever while noninfectious causes were responsible from fever in an important proportion of patients with underlying diseases.

scholarly journals Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs

2020 ◽  
Author(s):  
Zhe Li ◽  
Xin Li ◽  
Yi-You Huang ◽  
Yaoxing Wu ◽  
Runduo Liu ◽  
...  
Keyword(s):  
Free Energy ◽  
Virtual Screening ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Free Energy Perturbation ◽  
Hit Rate ◽  
Screening Approach ◽  
Main Protease ◽  
Energy Perturbation ◽  
Virtual Screening Approach

AbstractCoronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and, thus, repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. Here we report a new virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (Mpro). The accurate FEP-ABFE predictions were based on the use of a new restraint energy distribution (RED) function designed to accelerate the FEP-ABFE calculations and make the practical FEP-ABFE-based virtual screening of the existing drug library possible for the first time. As a result, out of twenty-five drugs predicted, fifteen were confirmed as potent inhibitors of SARS-CoV-2 Mpro. The most potent one is dipyridamole (Ki=0.04 μM) which has showed promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki=0.36 μM) and chloroquine (Ki=0.56 μM) were also found to potently inhibit SARS-CoV-2 Mpro for the first time. We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts.Significance StatementDrug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. It has been demonstrated that a new virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions can reach an unprecedently high hit rate, leading to successful identification of 16 potent inhibitors of SARS-CoV-2 main protease (Mpro) from computationally selected 25 drugs under a threshold of Ki = 4 μM. The outcomes of this study are valuable for not only drug repurposing to treat COVID-19, but also demonstrating the promising potential of the FEP-ABFE prediction-based virtual screening approach.

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