The incidence of 2019 novel corona virus (SARS-CoV-2) has created a medical emergency throughout the world. Various efforts have been made to develop the vaccine or effective treatments against the disease. The discovery of crystal structure of SARS-CoV-2 main protease has made the in silico identification of its inhibitors possible. Based on its critical role in viral replication, the viral protease can prove to be a promising “target” for antiviral drug therapy. We have systematically screened an in-house library of 15,754 natural and synthetic compounds, established at International Center for Chemical and Biological Sciences, University of Karachi. The in silico search for potential viral protease inhibitors resulted in nine top ranked ligands (compounds 1 – 9 ) against SARS-CoV-2 main protease (PDB ID: 6LU7) based on docking scores, and predictive binding energies. The in silico studies were updated via carrying out the docking, and predictive binding energy estimation, with a recently reported crystal structure of main protease (PDB ID: 6Y2F) at a better resolution i . e ., 1.95 Å. Compound 2 (molecular bank code AAA396) was found to have highest negative binding energy of −71.63 kcal/mol for 6LU7. While compound 3 (molecular bank code AAD146) exhibited highest negative binding energy of -81.92 kcal/mol for 6Y2F. The stability of the compounds- in complex with viral protease was analyzed by Molecular Dynamics simulation studies, and was found to be stable over the course of 20 ns simulation time. Compound 2, and 3 were predicted to be the significant inhibitors of SARS-CoV-2 3CL hydrolase (Mpro) among the nine short listed compounds.

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Background: Advanced glycation end products (AGEs) are known to be involved in the pathophysiology of diabetic complications, neurodegenerative diseases, and aging. Preventing the formation of AGEs can be helpful in the management of these diseases. Objective: Two classes of previously synthesized traizole Schiff’s bases (4H-1,2,4-triazole-4- Schiff’s bases 1-14, and 4H-1,2,4-triazole-3-Schiff’s bases 15-23) were evaluated for their in vitro antiglycation activity. Methods: In vitro fructose-mediated human serum albumin (HSA) glycation assay was employed to assess the antiglycation activity of triazole Schiff’s bases. The active compounds were subjected to cytotoxicity analysis by MTT assay on mouse fibroblast (3T3) cell line. Molecular docking and simulation studies were carried out to evaluate the interactions and stability of compounds with HSA. Anti-hyperglycemic and antioxidant activities of selected non-cytotoxic compounds were evaluated by in vitro α-glucosidase inhibition, and DPPH free radical scavenging assays, respectively. Results: Compound 1 (IC50=47.30±0.38 µM) from 4H-1,2,4-triazole-4-Schiff’s bases has exhibited antiglycation activity comparable to standard rutin (IC50=54.5±0.05 µM) along with a stable RMSD profile in MD simulation studies. Compound 1 also exhibited a potent α-glucosidase inhibitory activity, and moderate antioxidant property. Other derivatives showed a weak antiglycation activity with IC50 values between 248.1-637.7 µM. Compounds with potential antiglycation profile were found to be non-cytotoxic in a cellular assay. Conclusion: The study identifies triazole Schiff’s bases active against fructose-mediated glycation of HSA, thus indicates their potential against late diabetic complications due to production of advancedend products (AGEs).

Natural flora is the richest source of novel therapeutic agents due to their immense chemical diversity and novel biological properties. In this regard, eighteen natural products belonging to different chemical classes were evaluated for their thymidine phosphorylase (TP) inhibitory activity. TP shares identity with an angiogenic protein platelet derived endothelial cell growth factor (PD-ECGF). It assists tumor angiogenesis and is a key player in cancer progression, thus an ideal target to develop anti-angiogenic drugs. Eleven compounds 1–2, 5–10, 11, 15, and 18 showed a good to weak TP inhibitory activity (IC50 values between 44.0 to 420.3 μM), as compared to standards i.e. tipiracil (IC50 = 0.014 ± 0.002 μM) and 7-deazaxanthine (IC50 = 41.0 ± 1.63 μM). Kinetic studies were also performed on active compounds, in order to deduce the mechanism of ligand binding to enzyme. To get further insight into receptor protein (enzyme) and ligand interaction at atomic level, in- sillico studies were also performed. Active compounds were finally evaluated for cytotoxicity test against mouse fibroblast (3T3) cell line. Compound 18 (Masoprocol) showed a significant TP inhibitory activity (IC50 = 44.0 ± 0.5 μM). Kinetic studies showed that it inhibits the enzyme in a competitive manner (Ki = 25.6 ± 0.008 μM), while it adopts a binding pose different than the substrate thymidine. It is further found to be non-toxic in MTT cytotoxicity assay. This is the first report on TP inhibitory activity of several natural compounds, some of which may serve as leads for further research towards drug the development.

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Many Streptococci are characterized by the formation of long chains of cells. However, Streptococcus faecalis forms short chains of 4 to 6 cells or no chains at all, indicating that a cell-separating system must be active throughout the growth cycle. Although biochemically and serologically identical with typical S. faecalis, strain NCTC2400 forms long chains. Lominski, Cameron & Wyllie (1958), using Suramin (Bayer 205), stimulated typical S. faecalis to grow with long chains which were broken down by filtrates of ordinary cultures. Toennies et al. (1961) noted that the increasing speed of autolysis during exponential growth of S. faecalis corresponded to a decrease in average chain length of the cocci. Numerous other workers have also suggested that autolysins may be involved in cell separation (see for example Tomasz, 1968 ; Chatterjee et al. 1969 ; Fan, 19700, b; Soper & Winter, 1973). The autolysin in S. faecalis occurs in the region of the septum and of the most recently deposited wall, and is produced maximally during the period of exponential growth (Shockman, Pooley & Thompson, 1967; Higgins, Pooley & Shockman, 1970). It is an endo-Nacetylmuramidase which hydrolyses the ,8-I ,4 bonds between N-acetylmuramic acid and N-acetylglucosamine (Shockman, Thompson & Conover, 1967) and may be necessary for the growth and extension of the mucopeptide in the wall (Pooley & Shockman, 1970). This investigation examines the effect of supernatant fluids from short-chain cultures of S. faecah on the long-chain variant S. faecalis NCTC2400.