Identification of potential inhibitors of three key enzymes of SARS-CoV2 using computational approach.

The recent outbreak of coronavirus disease-19 (COVID-19) continues to drastically affect healthcare throughout the world. To date, no approved treatment regimen or vaccine is available to effectively attenuate or prevent the infection. Therefore, collective and multidisciplinary efforts are needed to identify new therapeutics or to explore effectiveness of existing drugs and drug-like small molecules against SARS-CoV-2 for lead identification and repurposing prospects. This study addresses the identification of small molecules that specifically bind to any of the three essential proteins (RdRp, 3CL-protease and helicase) of SARS-CoV-2. By applying computational approaches we screened a library of 4574 compounds also containing FDA-approved drugs against these viral proteins. Shortlisted hits from initial screening were subjected to iterative docking with the respective proteins. Ranking score on the basis of binding energy, clustering score, shape complementarity and functional significance of the binding pocket was applied to identify the binding compounds. Finally, to minimize chances of false positives, we performed docking of the identified molecules with 100 irrelevant proteins of diverse classes thereby ruling out the non-specific binding. Three FDA-approved drugs showed binding to 3CL-protease either at the catalytic pocket or at an allosteric site related to functionally important dimer formation. A drug-like molecule showed binding to RdRp in its catalytic pocket blocking the key catalytic residues. Two other drug-like molecules showed specific interactions with helicase at a key domain involved in catalysis. This study provides lead drugs or drug-like molecules for further in vitro and clinical investigation for drug repurposing and new drug development prospects.

Amino acid conjugated antimicrobial drugs: Synthesis, lipophilicity- activity relationship, antibacterial and urease inhibition activity.

Present work describes the in vitro antibacterial evaluation of some new amino acid conjugated antimicrobial drugs. Structural modification was attempted on the three existing antimicrobial pharmaceuticals namely trimethoprim, metronidazole, isoniazid. Twenty one compounds from seven series of conjugates of these drugs were synthesized by coupling with some selected Boc-protected amino acids. The effect of structural features and lipophilicity on the antibacterial activity was investigated. The synthesized compounds were evaluated against five standard American type culture collection (ATCC) i.e. Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi strains of bacteria. Our results identified a close relationship between the lipophilicity and the activity. Triazine skeleton proved beneficial for the increase in hydrophobicity and potency. Compounds with greater hydrophobicity have shown excellent activities against Gram-negative strains of bacteria than Gram-positive. 4-amino unsubstituted trimethoprim-triazine derivative 7b have shown superior activity with MIC = 3.4 µM (2 µg/mL) for S. aureus and 1.1 µM (0.66 µg/mL) for E. coli. The synthesized compounds were also evaluated for their urease inhibition study. Microbial urease from Bacillus pasteurii was chosen for this study. Triazine derivative 7a showed excellent inhibition with IC50 = 6.23 ±â€¯0.09 µM. Docking studies on the crystal structure of B. pasteurii urease (PDB ID 4UBP) were carried out.

Current understanding of treatment and management protocol for adult diabetic in-patients at a tertiary care hospital.

OBJECTIVE: To assess the current understanding of treatment and management protocols for adult diabetic inpatients at a tertiary care hospital. METHODS: This cross-sectional study, conducted at the Civil Hospital Karachi from July to September 2009, involved 450 participants, who were interviewed through a well-structured questionnaire regarding the patient's demography, clinical features, past medical history, type of diabetes mellitus, duration, associated complications, and also involved patient notes for laboratory tests and management. SPSSv15.0 was used for descriptive analysis. RESULTS: The study population of 450 diabetics had 144 (32%) males and 306 (68%) females. Of the total, 435 (96.7%) patients had type 2 diabetes. There were 231 (51%) patients using insulin, 168 (37.3%) oral hypoglycaemic drugs, and 51 (11.3%) using both. Among patients using insulin, regular insulin usage stood at 30% followed by a combination of regular insulin and NPH (26.7%) and NPH alone at 6%. The most popular drug used was metformin (27.3%) and the least used drug was glitazones (4%). In the study population, 73.3% patients controlled their diabetes with diet, and 24.7% with regular exercise. CONCLUSION: Majority of the study population had type 2 diabetes with a female preponderance. Insulin was prescribed for half the patients. Metformin was the most frequently used oral hypoglycaemic drug.