Screening of FDA Approved Drugs Against SARS-CoV-2 Main Protease: Coronavirus Disease.

At the end of December 2019, a new strain of coronavirus was identified in the Wuhan city of Hubei province in China. Within a shorter period of time, an unprecedented outbreak of this strain was witnessed over the entire Wuhan city. This novel coronavirus strain was later officially renamed as COVID-19 (Coronavirus disease 2019) by the World Health Organization. The mode of transmission was human-to-human contact and hence resulted in a rapid surge across the globe where more than 24 million people have been infected with COVID-19. In the current scenario, finding potent drug candidates for the treatment of COVID-19 has emerged as the most challenging task for clinicians and researchers worldwide. Identification of new drugs and vaccine development may take from a few months to years based on the clinical trial processes. To overcome the several limitations involved in identifying and bringing out potent drug candidates for treating COVID-19, in the present study attempts were made to screen the FDA approved drugs using High Throughput Virtual Screening (HTVS). The COVID-19 main protease (COVID-19 Mpro) was chosen as the drug target for which the FDA approved drugs were initially screened with HTVS. The drug candidates that exhibited favorable docking score, energy, and emodel calculations were further taken for performing Induced Fit Docking (IFD) using Schrodinger's GLIDE. From the flexible docking results, the following four FDA approved drugs Sincalide, Pentagastrin, Ritonavir, and Phytonadione were identified. In particular, Sincalide and Pentagastrin can be considered potential key players for the treatment of COVID-19 disease.

Efficacy of Antimicrobial and Larvicidal Activities of Green Synthesized Silver Nanoparticles Using Leaf Extract of Plumbago auriculata Lam.

This work reports the synthesis of silver nanoparticles (AgNPs) using aqueous extract of Plumbago auriculata, and evaluates their antibacterial and larvicidal activities. The synthesized silver nanoparticles were characterized by various spectroscopy techniques, such as FTIR, XRD, TEM, EDX, Zeta potential, and DLS. The synthesized AgNPs exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria, such as Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae. Furthermore, synthesized nanoparticles inhibited the fourth instars larvae of Aedes aegypti and Culex quinquefasciatus at the concentration of 45.1 and 41.1 µg/mL respectively. Results of dose-dependent studies showed that synthesized nanoparticles were also effective at low concentrations. Molecular docking studies performed with the salivary protein and odorant-binding protein of Aedes aegypti and Culex quinquefasciatus demonstrated that the naphthoquinone compound plumbagin exhibited reliable binding affinity towards the two enzymes. The findings thus reveal that the plant extract and its nanoparticles can be a better alternative to available chemicals to control mosquitos.

Repurposing Cancer Drugs Batimastat and Marimastat to Inhibit the Activity of a Group I Metalloprotease from the Venom of the Western Diamondback Rattlesnake, Crotalus atrox.

Snakebite envenomation causes over 140,000 deaths every year, predominantly in developing countries. As a result, it is one of the most lethal neglected tropical diseases. It is associated with incredibly complex pathophysiology due to the vast number of unique toxins/proteins present in the venoms of diverse snake species found worldwide. Here, we report the purification and functional characteristics of a Group I (PI) metalloprotease (CAMP-2) from the venom of the western diamondback rattlesnake, Crotalus atrox. Its sensitivity to matrix metalloprotease inhibitors (batimastat and marimastat) was established using specific in vitro experiments and in silico molecular docking analysis. CAMP-2 shows high sequence homology to atroxase from the venom of Crotalus atrox and exhibits collagenolytic, fibrinogenolytic and mild haemolytic activities. It exerts a mild inhibitory effect on agonist-induced platelet aggregation in the absence of plasma proteins. Its collagenolytic activity is completely inhibited by batimastat and marimastat. Zinc chloride also inhibits the collagenolytic activity of CAMP-2 by around 75% at 50 µM, while it is partially potentiated by calcium chloride. Molecular docking studies have demonstrated that batimastat and marimastat are able to bind strongly to the active site residues of CAMP-2. This study demonstrates the impact of matrix metalloprotease inhibitors in the modulation of a purified, Group I metalloprotease activities in comparison to the whole venom. By improving our understanding of snake venom metalloproteases and their sensitivity to small molecule inhibitors, we can begin to develop novel and improved treatment strategies for snakebites.

Preliminary analysis to target pyruvate phosphate dikinase from wolbachia endosymbiont of Brugia malayi for designing anti-filarial agents.

Filariasis causing nematode Brugia malayi is shown to harbor wolbachia bacteria as symbionts. The sequenced genome of the wolbachia endosymbiont from B.malayi (wBm) offers an unprecedented opportunity to identify new wolbachia drug targets. Genome analysis of the glycolytic/gluconeogenic pathway has revealed that wBm lacks pyruvate kinase (PK) and may instead utilize the enzyme pyruvate phosphate dikinase (PPDK; ATP: pyruvate, orthophosphate phosphotransferase, EC 2.7.9.1). PPDK catalyses the reversible conversion of AMP, PPi and phosphoenolpyruvate into ATP, Pi and pyruvate. Most organisms including mammals exclusively possess PK. Therefore the absence of PPDK in mammals makes this enzyme as attractive wolbachia drug target. In the present study we have modeled the three dimensional structure of wBm PPDK. The template with 50% identity and 67% similarity in amino acid sequence was employed for homology-modeling approach. The putative active site consists of His476, Arg360, Glu358, Asp344, Arg112, Lys43 and Glu346 was selected as site of interest for designing suitable inhibitor molecules. Docking studies were carried out using induced fit algorithms with OPLS force field of Schrödinger's Glide. The lead molecules which inhibit the PPDK activity are taken from the small molecule library (Pubchem database) and the interaction analysis showed that these compounds may inhibit the function of PPDK in wBm.