Oleuropein as a Potent Compound against Neurological Complications Linked with COVID-19: A Computational Biology Approach.

The association of COVID-19 with neurological complications is a well-known fact, and researchers are endeavoring to investigate the mechanistic perspectives behind it. SARS-CoV-2 can bind to Toll-like receptor 4 (TLR-4) that would eventually lead to α-synuclein aggregation in neurons and stimulation of neurodegeneration pathways. Olive leaves have been reported as a promising phytotherapy or co-therapy against COVID-19, and oleuropein is one of the major active components of olive leaves. In the current study, oleuropein was investigated against SARS-CoV-2 target (main protease 3CLpro), TLR-4 and Prolyl Oligopeptidases (POP), to explore oleuropein potency against the neurological complications associated with COVID-19. Docking experiments, docking validation, interaction analysis, and molecular dynamic simulation analysis were performed to provide insight into the binding pattern of oleuropein with the three target proteins. Interaction analysis revealed strong bonding between oleuropein and the active site amino acid residues of the target proteins. Results were further compared with positive control lopinavir (3CLpro), resatorvid (TLR-4), and berberine (POP). Moreover, molecular dynamic simulation was performed using YASARA structure tool, and AMBER14 force field was applied to examine an 100 ns trajectory run. For each target protein-oleuropein complex, RMSD, RoG, and total potential energy were estimated, and 400 snapshots were obtained after each 250 ps. Docking analyses showed binding energy as -7.8, -8.3, and -8.5 kcal/mol for oleuropein-3CLpro, oleuropein-TLR4, and oleuropein-POP interactions, respectively. Importantly, target protein-oleuropein complexes were stable during the 100 ns simulation run. However, an experimental in vitro study of the binding of oleuropein to the purified targets would be necessary to confirm the present study outcomes.

Dithymoquinone Analogues as Potential Candidate(s) for Neurological Manifestation Associated with COVID-19: A Therapeutic Strategy for Neuro-COVID.

The COVID-19 era has prompted several researchers to search for a linkage between COVID-19 and its associated neurological manifestation. Toll-like receptor 4 (TLR-4) acts as one such connecting link. spike protein of SARS-CoV-2 can bind either to ACE-2 receptors or to TLR-4 receptors, leading to aggregation of α-synuclein and neurodegeneration via the activation of various cascades in neurons. Recently, dithymoquinone has been reported as a potent multi-targeting candidate against SARS-CoV-2. Thus, in the present study, dithymoquinone and its six analogues were explored to target 3CLpro (main protease of SARS-CoV-2), TLR4 and PREP (Prolyl Oligopeptidases) by using the molecular docking and dynamics approach. Dithymoquinone (DTQ) analogues were designed in order to investigate the effect of different chemical groups on its bioactivity. It is noteworthy to mention that attention was given to the feasibility of synthesizing these analogues by a simple photo-dimerisation reaction. The DTQ analogue containing the 4-fluoroaniline moiety [Compound (4)] was selected for further analysis by molecular dynamics after screening via docking-interaction analyses. A YASARA structure tool built on the AMBER14 force field was used to analyze the 100 ns trajectory by taking 400 snapshots after every 250 ps. Moreover, RMSD, RoG, potential energy plots were successfully obtained for each interaction. Molecular docking results indicated strong interaction of compound (4) with 3CLpro, TLR4 and PREP with a binding energy of -8.5 kcal/mol, -10.8 kcal/mol and -9.5 kcal/mol, respectively, which is better than other DTQ-analogues and control compounds. In addition, compound (4) did not violate Lipinski's rule and showed no toxicity. Moreover, molecular dynamic analyses revealed that the complex of compound (4) with target proteins was stable during the 100 ns trajectory. Overall, the results predicted that compound (4) could be developed into a potent anti-COVID agent with the ability to mitigate neurological manifestations associated with COVID-19.

Quality of Hypertension Management in Type 2 Diabetes in India: A Multisite Prescription Audit.

BACKGROUND AND OBJECTIVE: Renin-angiotensin system (RAS) blockers (angiotensin converting enzyme inhibitors ACEI, angiotensin receptor blockers, ARB) are preferred drugs to control hypertension among diabetic patients. To determine frequency of RAS blocker use in hypertensive patients with type 2 diabetes, we performed a multisite study in India. METHODS: We evaluated physician prescriptions in consecutive patients with type 2 diabetes at 9 sites in India. Details of socio-demographic characteristics, clinical findings and prescription medicines were obtained. Descriptive statistics are reported. RESULTS: Hypertension treatment details were available in 8056 of 8699 diabetic patients (4829 men, 3227 women). No hypertension was in 3300 (40.9%), hypertension in 3625 (45.0%), and hypertension with vascular disease in 1131 (14.0%). In diabetics with no hypertension, hypertension, and hypertension with vascular disease, respectively, prescriptions of antihypertensive drugs was: RAS blockers in 19.4, 48.2 and 58.1%, beta-blockers in 4.8, 31.6 and 38.8%, calcium channel blockers in 0.4, 27.4 and 14.3% and diuretics in 0.6, 36.4 and 17.1%. ACEIs were prescribed more frequently than ARB's in hypertensive diabetics (60.7 vs 39.2%) as well as in diabetics with vascular disease (58.6 vs 41.4%). In diabetics with hypertension (n=3625) prescription of one, two or three antihypertensive drugs was 49.8%, 33.7% and 3.5% while statins were prescribed in 54.1%. CONCLUSION: Use of RAS blockers (ACEI or ARB) in uncomplicated as well as complicated hypertensive patients with type 2 diabetes is sub-optimal. Most of the patients are on one drug and prescription of ≥3 drugs are rare. Statins are prescribed in only a half.