In silico approach for the development of novel antiviral compounds based on SARS-COV-2 protease inhibition.

The COVID-19 pandemic emerged in 2019, bringing with it the need for greater stores of effective antiviral drugs. This paper deals with the conformation-independent, QSAR model, developed by employing the Monte Carlo optimization method, as well as molecular graphs and the SMILES notation-based descriptors for the purpose of modeling the SARS-CoV-3CLpro enzyme inhibition. The main purpose was developing a reproducible model involving easy interpretation, utilized for a quick prediction of the inhibitory activity of SAR-CoV-3CLpro. The following statistical parameters were present in the best-developed QSAR model: (training set) R 2 = 0.9314, Q 2 = 0.9271; (test set) R 2 = 0.9243, Q 2 = 0.8986. Molecular fragments, defined as SMILES notation descriptors, that have a positive and negative impact on 3CLpro inhibition were identified on the basis of the results obtained for structural indicators, and were applied to the computer-aided design of five new compounds with (4-methoxyphenyl)[2-(methylsulfanyl)-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazol-1-yl]methanone as a template molecule. Molecular docking studies were used to examine the potential inhibition effect of designed molecules on SARS-CoV-3CLpro enzyme inhibition and obtained results have high correlation with the QSAR modeling results. In addition, the interactions between the designed molecules and amino acids from the 3CLpro active site were determined, and the energies they yield were calculated. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-022-02170-8.

Melatonin modulates acute cardiac muscle damage induced by carbon tetrachloride - involvement of oxidative damage, glutathione, and arginine and nitric oxide metabolism.

The present study was designed to evaluate the cardioprotective effects of melatonin (a single dose of 50 mg·kg-1), a naturally occurring polypharmacological molecule, in Wistar rats acutely exposed to carbon tetrachloride (CCl4). This was done for the first time by tracking different biochemical parameters that reflect rat heart antioxidative and oxidative capacities, nitric oxide and arginine metabolism, and the glutathione cycle. Additionally, the extrinsic apoptosis pathway related parameters were studied. Acute exposure to CCl4 led to an increase in the studied tissue oxidant parameters (hydrogen peroxide, malondialdehyde, and carbonylated protein content), as well as the activity alteration of antioxidant (catalase, superoxide dismutase, and peroxidase) and glutathione-metabolizing (glutathione peroxidase, S-transferase, and reductase) enzymes. Furthermore, CCl4 caused a disturbance in the tissue myeloperoxidase, nitric oxide, citrulline, arginase, and inducible nitric oxide synthase content and activities and in two apoptosis-related parameters, caspase-3 and FAS ligand. Melatonin as a post-treatment prevented the changes induced by CCl4 to a differing extent, and in some cases, it was so potent that it completely abolished any tissue disturbances. This study is a promising starting point for further research directed to the development of melatonin treatment in cardiac tissue associated diseases.

Pain, Physical Function, Radiographic Features, and Quality of Life in Knee Osteoarthritis Agricultural Workers Living in Rural Population.

Background: The aim of this study was to analyse the relationship between the clinical manifestations, disease severity based on radiography images, functional activity level, and quality of life in patients with knee osteoarthritis in a rural population living in Serbian enclaves in Kosovo, as well as to determine the correlation between the WOMAC and the EQ-5D questionnaire in this population. Method: The cross-sectional study was conducted at the Internal Medicine Clinic, Clinical Hospital Center Pristina-Gracanica, located in Laplje Selo from February to December 2013. One hundred patients with confirmed (American College of Rheumatology criteria) knee osteoarthritis completed the EQ-5D and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaires, rated pain on a visual analogue scale (VAS), and underwent knee radiographic examinations. Result: Most patients were obese with moderate radiographic changes according to the Kellgeren-Lawrence scale and suffered from very severe pain according to the VAS scale. The duration of disease significantly correlated with the WOMAC scores, VAS score, and all of the scores on the EQ-5D, except for mobility. The age of participants showed a similar correlation with the same variables. The patients with higher Kellgren-Lawrence scores (3-4) were significantly older, with a significantly higher body mass index (BMI) and longer duration of disease than patients with lower scores (1-2). Significantly higher VAS, pain/discomfort EQ-5D, and WOMAC pain and function scores were also recorded among patients with more significant radiological changes. The correlations between WOMAC and EQ-5D were satisfactory. Conclusion: The severity of clinical manifestations and radiographic area changes may affect functional ability and the quality of life in knee OA patients living in rural areas, which requires adequate treatment and physical therapy.