Pharmacoinformatics-based identification of transmembrane protease serine-2 inhibitors from Morus Alba as SARS-CoV-2 cell entry inhibitors

Abstract: Transmembrane protease serine-2 (TMPRSS2) is a cell-surface protein expressed by epithelial cells of specific tissues including those in the aerodigestive tract. It helps the entry of novel coronavirus (n-CoV) or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the host cell. Successful inhibition of the TMPRSS2 can be one of the crucial strategies to stop the SARS-CoV-2 infection. In the present study, a set of bioactive molecules from Morus alba Linn. were screened against the TMPRSS2 through two widely used molecular docking engines such as Autodock vina and Glide. Molecules having a higher binding affinity toward the TMPRSS2 compared to Camostat and Ambroxol were considered for in-silico pharmacokinetic analyses. Based on acceptable pharmacokinetic parameters and drug-likeness, finally, five molecules were found to be important for the TMPRSS2 inhibition. A number of bonding interactions in terms of hydrogen bond and hydrophobic interactions were observed between the proposed molecules and ligand-interacting amino acids of the TMPRSS2. The dynamic behavior and stability of best-docked complex between TRMPRSS2 and proposed molecules were assessed through molecular dynamics (MD) simulation. Several parameters from MD simulation have suggested the stability between the protein and ligands. Binding free energy of each molecule calculated through MM-GBSA approach from the MD simulation trajectory suggested strong affection toward the TMPRSS2. Hence, proposed molecules might be crucial chemical components for the TMPRSS2 inhibition. Graphic abstract: [Figure not available: see fulltext.

Assessment of acute and sub-chronic neurotoxicity of Morus alba L. fruits in rodents

Abstract Background Morus alba L. fruits are consumed since long for their nutritional and medicinal values. Although there were studies on the neuroprotective activity of the fruit extract, safety profile of the fruit extract is not yet explored as per the recommended standard guidelines over the central nervous system (CNS). The present work was aimed to assess the neurotoxicity profile of chemically characterized extract of M. alba L. fruits (MA) using validated OECD guidelines, i.e., 425 and 424 in rodents. Results Neurobehavioural parameters were examined for motor, sensory and behavioural responses using actophotometer, hot plate and light and dark box test, respectively as per OECD 424. Interestingly, no sign of mortality and/or adversity on mice treated per-orally with MA (2000 mg/kg) was observed during the limit test as per OECD 425. Further, rats treated with MA (1000, 300 and 100 mg/kg, p.o.) for 28 days, showed insignificant (p &lt; 0.05) changes in body weight, food consumption, neurobehavioural responses, organ weights and biochemical, haematological and histopathological features when compared with vehicle-treated animals. Conclusion The outcome of findings suggests that MA is safe in acute oral as well as sub-chronic (28 days) administration in mice and rats respectively. MA (1000 mg/kg) did not pose any toxic sign and symptoms on neurobehavioural responses in rats even after 28 days repeated treatment in compliance with OECD 424. </jats:sec

Diurnal Variation in the Mortality of Section Patients with COVID-19 Pneumonia: A Retrospective Study

Introduction: Coronavirus Disease 2019 (COVID-19), the new contagious novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), pandemic in 2020-21 has had a devastating impact on human race. The most common cause of death among hospitalised patient was COVID-19 pneumonia or lung injury. Various studies have shown diurnal variation in human mortality due to all causes with or without intervention. Aim: To identify existence of diurnal variations for mortality among the hospitalised patients with COVID-19 pneumonia. Materials and Methods: This hospital-record based, retrospective study was conducted in a tertiary referral centre of north east India (Assam Medical College, Dibrugarh, Assam, India) which was a dedicated COVID-19 hospital during the pandemic. The study was conducted from September 2021 to December 2021 and the data was collected and recorded from the Cadaver slips issued to families of patient dying of COVID-19 pneumonia during the period January 2021 to August 2021. The data were generated by plotting the number of deaths of COVID-19 cases for each two hour interval as a percent of the mean number of deaths per twohour interval and as a percentage of cumulative deaths per twohour interval on a 24 hour scale. The deaths were sub grouped according to gender, age, and reported co-morbid causes of death along with pneumonia. Comparisons of data i.e., mean deaths/2 hour interval (mean±SD) were performed by one-way Analysis of Variance (ANOVA), followed by Bartlett's test for equal variances. The p-value &lt;0.05 was considered as statistically significant. Results: Total 743 deaths, with 537 males and 206 females were included in the study. Mean age of the deaths was 56.39 years. There was rise of deaths during 4 PM to 6 PM (16:00 to 18:00) interval for all deaths due to COVID-19 pneumonia. The increase in deaths during this period was mainly due to deaths among males equal or above 65 years and females below age 65 years. However, the deaths of females equal or above the age of 65 years did not show significant diurnal variation. Only 26.51% (n=197) of pneumonia deaths were without co-morbidity. Conclusion: There exists a diurnal variation in mortality among COVID-19 pneumonia patients with evening rise of deaths. Diurnal variation is significantly more among males rather than females above 65 years.</jats:p

Pharmacognostical characterization and in vitro antioxidant activity of Acacia pennata (L.) Willd. leaves: A Southeast Asian medicinal plant

Pre-defined analytical features of a plant are used as a reference to aid in accurate identification, proper standardization, and quality control. However, no systematic work on the leaves of A. pennata is available for reference to check its authenticity, purity, and quality. Therefore, the study was aimed to develop pharmacognostic parameters using standard guidelines. The work provides macroscopic, qualitative and quantitative microscopic, physicochemical parameters, chromatographic fingerprint profile, and in-vitro antioxidant activity of A. pennata. Preliminary phytochemical screening and thin-layer chromatography hints the presence of steroids and glycosides along with polyphenolic compounds viz. phenols and flavonoids. Quantification of polyphenolic phytoconstituents and assessment of in-vitro antioxidant activity of the methanolic extract was done. The current communication offers referential knowledge on the analytical and diagnostic features for accurate taxonomical identification, proper characterization and will also help in the establishment of a pharmacognostic monograph of A. pennata for effective quality control.</jats:p

COVID-19 incidence in Mizoram, India

COVID-19 had ravaged the physical and mental health of millions of people globally. With more than 18 million infections and 0.7 million fatalities worldwide, the pandemic showed no signs of slowing down. Since the detection of the first COVID-19 case in Mizoram, there is still no scientific record of the incidence of the disease. Therefore, the aim of this report is to produce the first scientific documentation of COVID-19 in Mizoram. As on 6 August 2020, a total of 537 cases have been reported with a recovery rate of 53.63%. Voluntary services of local community to fully support the authority are unique and worth to mention. Many people, from layman to technically qualified persons, volunteered themselves to fight the spread of the disease in the state. No death is yet reported although the doubling rate of COVID-19 case was 14.66 days. Aizawl district recorded the highest case (61.08%) followed by Lunglei and Siaha districts. Weekly data analysis showed the outbreak occurred in the 11th week (second week of June) since the nationwide lockdown in March 2020. The incidence is higher in males than in females. The infected age group ranged from 28–43 years in males and 22–33 years in females. The youngest and oldest infected age was 1 and 64 respectively. There is still no community transmission although this could occurr at any moment. This report may possibly serve as a referential scientific literature to aid the retrospective and prospective studies of COVID-19 in Mizoram.</jats:p

Evaluation of Anti-Diabetic and Anti-Hyperlipidemic Activity of Isolated Bioactive Compounds of Leaves of Annona reticulata Linn.

Background: The leaves of Annona reticulata Linn. have been traditionally used by the tribes of Assam as a source of medicine to mitigate a range of health ailments, including diabetes and obesity. Objectives: The current study aimed to evaluate the anti-diabetic and anti-hyperlipidemic potential of bioactive fractions isolated from the methanolic extract of Annona reticulata Linn. leaves using Nicotinamide + Streptozotocin (60 mg/kg, i.p.) induced diabetic rats. Methods: The partially purified bioactive fractions, namely F1, F2, F3 and F4 were administered to diabetic rats with a dose of 200 mg/kg, per oral (p.o.) and the effect of the fractions on serum glucose was studied up to 21 days. The potent fractions were further subjected to spectral analysis for the identification of the isolated active compounds. Results: The in-vivo anti-diabetic activity of the isolated fractions F2 and F3 was found significant controlling blood glucose level, alike glibenclamide. Interestingly, F2 and F3 treated animals were found significant in restoring the lipid and liver enzymes profile in streptozotocin challenge rats. Further, spectral analysis revealed that F2 and F3 were comprised of Quercetin and Gallic acid, respectively. Conclusion: The outcome of finding demonstrates the anti-diabetic and anti-hyperlipidemic potential of the isolates/fractions of A. reticulata, which were found enriched in polyphenolics, including Quercetin and Gallic acid; and provided logistic behind the traditional use of the A. reticulata against diabetes and obesity. </jats:sec

Computational guided identification of potential leads from Acacia pennata (L.) Willd. as inhibitors for cellular entry and viral replication of SARS-CoV-2

Abstract Background Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in 2019 and is still an on-going pandemic. SARS-CoV-2 uses a human protease called furin to aid in cellular entry and its main protease (Mpro) to achieve viral replication. By targeting these proteins, scientists are trying to identify phytoconstituents of medicinal plants as potential therapeutics for COVID-19. Therefore, our study was aimed to identify promising leads as potential inhibitors of SARS-CoV-2 Mpro and furin using the phytocompounds reported to be isolated from Acacia pennata (L.) Willd. Results A total of 29 phytocompounds were reported to be isolated from A. pennata. Molecular docking simulation studies revealed 9 phytocompounds as having the top 5 binding affinities towards SARS-CoV-2 Mpro and furin. Among these phytocompounds, quercetin-3-O-α-L-rhamnopyranoside (C_18), kaempferol 3-O-α-L-rhamnopyranosyl-(1 → 4)-β-D-glucopyranoside (C_4), and isovitexin (C_5) have the highest drug score. However, C_18 and C_4 were not selected for further studies due to bioavailability issues and low synthetic accessibility. Based on binding affinity, molecular properties, drug-likeness, toxicity parameters, ligand interactions, bioavailability, synthetic accessibility, structure–activity relationship, and comparative analysis of our experimental findings with other studies, C_5 was identified as the most promising phytocompound. C_5 interacted with the active site residues of SARS-CoV-2 Mpro (GLU166, ARG188, GLN189) and furin (ASN295, ARG298, HIS364, THR365). Many phytocompounds that interacted with these amino acid residues were reported by other studies as potential inhibitors of SARS-CoV-2 Mpro and furin. The oxygen atom at position 18, the –OH group at position 19, and the 6-C-glucoside were identified as the pharmacophores in isovitexin (also known as apigenin-6-C-glucoside). Other in-silico studies reported apigenin as a potential inhibitor of SARS-CoV-2 Mpro and apigenin-o-7-glucuronide was reported to show stable conformation during MD simulations with SARS-CoV-2 Mpro. Conclusion The present study found isovitexin as the most promising phytocompound to potentially inhibit the cellular entry and viral replication of SARS-CoV-2. We also conclude that compounds having oxygen atom at position 18 (C-ring), –OH group at position 19 (A-ring), and 6-C-glucoside attached to the A-ring at position 3 on a C6–C3–C6 flavonoid scaffold could offer the best alternative to develop new leads against SARS-CoV-2. </jats:sec