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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been responsible for the cause of global pandemic Covid-19 and to date, there is no effective treatment available. The spike ‘S’ protein of SARS-CoV-2 and ACE2 of the host cell are being targeted to design new drugs to control Covid-19. Similarly, a transmembrane serine protease, TMPRSS2 of the host cell plays a significant role in the proteolytic cleavage of viral ‘S’ protein helpful for the priming of ACE2 receptors and viral entry into human cells. However, three-dimensional structural information and the inhibition mechanism of TMPRSS2 is yet to be explored experimentally. Hence, we have used a molecular dynamics (MD) simulated homology model of TMPRSS2 to study the inhibition mechanism of experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride (BHH) using molecular modeling techniques. Prior to docking, all three inhibitors were geometry optimized by semi-empirical quantum chemical RM1 method. Molecular docking analysis revealed that Camostat mesylate and its structural analogue Nafamostat interact strongly with residues His296 and Ser441 present in the catalytic triad of TMPRSS2, whereas BHH binds with Ala386 along with other residues. Comparative molecular dynamics simulations revealed the stable behavior of all the docked complexes. MM-PBSA calculations also revealed the stronger binding of Camostat mesylate to TMPRSS2 active site residues as compared to Nafamostat and BHH. Thus, this structural information could be useful to understand the mechanistic approach of TMPRSS2 inhibition, which may be helpful to design new lead compounds to prevent the entry of SARS-Coronavirus 2 in human cells.

The rapid outbreak of SARS-Coronavirus 2 (SARS-CoV-2) caused a serious global public health threat. The spike ‘S’ protein of SARS-CoV-2 and ACE2 of the host cell are being targeted to design and discover new drugs to control Covid-19 disease. Similarly, a transmembrane serine protease, TMPRSS2 of the host cell has been found to play a significant role in proteolytic cleavage of viral spike protein priming to the receptor ACE2 present in human cell. However, three dimensional structure and inhibition mechanism of TMPRSS2 is yet to be explored experimentally. Hence, in the present study we have generated a homology model of TMPRSS2 and studied its binding properties with experimentally studied inhibitors viz. Camostat mesylate, Nafamostat and Bromhexine hydrochloride (BHH) using molecular docking technique. Docking analysis revealed that the Camostat mesylate and its structural analogue Nafamostat interacts strongly with residues His296, Ser441 and Asp435 present in catalytic triad of TMPRSS2. However, BHH interacts with Gln438 and other residues present in the active site pocket of TMPRSS2 through hydrophobic contacts effectively. Thus, these results revealed the inhibition mechanism of TMPRSS2 by known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride in detail at the molecular level. However, Camostat mesylate shows strong binding as compared to other two inhibitors. This structural information could also be useful to design and discover new inhibitors of TMPRSS2, which may be helpful to prevent the entry to SARS-Coronavirus 2 in human cell.

Objective To investigate the combinatorial effect of hydroalcoholic extracts of Andrographis paniculata Nees. and Pterocarpus marsupium Roxb. plants prospective to diabetes management. Methods Taking a lead from the scientific literature, in silico studies have also been designed for the screening of anti-diabetic targets against andrographolide and pterostilbene compounds followed by in vivo studies from Andrographis paniculata Nees. and Pterocarpus marsupium Roxb. Furthermore, the diabetes was induced by STZ model and the impact of Andrographis paniculata Nees. and Pterocarpus marsupium Roxb. have been conformed by relative expression studies by qPCR. Results Our results have shown that andrographolide and pterostilbene are SGLT2 inhibitors and selective PPARγ agonists in in silico studies. Later, during in vivo mRNA expression studies confirming the same pattern. The findings of the study has shown to overcome the common knowledge of the only C–glycoside based molecules inhibiting the SGLT2. Conclusions The possible mechanism for PtyroneTM in the management of diabetes could be a selective PPARγ agonist, GLUT4 translocation and SGLT2 inhibition molecule.

Importance: This post-marketing surveillance study was conducted to evaluate real-world information about the efficacy and safety of oral Tinefcon? tablets (Sphaeranthus indicus based) in plaque psoriasis patients. Materials and Methods: Patients aged at least 18 years and older with clinical diagnosis of plaque psoriasis, were enrolled in this open label, non-comparative, multicenter trial. All eligible subjects received four 700 mg Tinefcon? tablets/day for 12 weeks. The primary outcome measure was percent change in Psoriasis Area Severity Index (PASI) score from baseline to week 12. The secondary outcome measures were Physician Global Assessment (PGA), Nail Psoriasis Severity Index (NAPSI), Psoriatic Arthritis Evaluation and Gene Expression Profiling and Immunohistochemistry. Results: After completion of Tinefcon? treatment at 12 weeks, more than half of subjects (52%) achieved PASI 50 response; PASI 75 response was attained in 68 (23%) subjects and PASI 90 response in 22 (7%) subjects. Five subjects with severe psoriasis achieved PASI 90 without receiving any concomitant medication. Reduction in severity as assessed by PGA was observed in more than half of patients with moderate disease. Histopathological evaluation revealed that epidermal thickness was considerably reduced in 66% of subjects. The expression of inflammatory marker S100A9 protein was(meaningfully reduced in 60% patients with non-significant reduction of Keratin 10 protein expression. Gene expression analysis showed increase down regulation of SERPINB4; PI3 and KRT16 genes after a 12-week treatment period in subjects with higher PASI scores. Conclusion: Oral Tinefcon? tablets showed good efficacy and had a favorable safety profile in plaque psoriasis patients.