Identification, virtual screening and molecular dynamic analysis of novel TMPRSS2 inhibitors from natural compound database as potential entry-blocking agents in SARS-CoV-2 therapy.

Scientific insights gained from the severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS) outbreaks have been assisting scientists and researchers in the quest of antiviral drug discovery process against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronaviruses and influenza viruses both rely on the host type 2 transmembrane serine protease, TMPRSS2, for entry and propagation. Recent studies report SARS-CoV-2 also uses TMPRSS2 to enter cells. In the current study, we employed structure-based virtual screening of 1,82,651 natural compounds downloaded from the zin database against the homology model of the TMPRSS2 protein, followed by a molecular dynamics-based simulation to identify potential TMPRSS2 hits. The virtual screening yielded 110 hits with docking scores ranging from -8.654 to -6.775 and glide energies ranging from -55.714 to -29.065 kcal/mol. The binding mode analysis revealed that the hit molecules made H-bond, Pi-Pi stacking and salt bridge contacts with the TMPRSS2 active site residues. MD simulations of the top two hits (ZINC000095912839 and ZINC000085597504) revealed to form a stable complex with TMPRSS2, with a minimal RMSD and RMSF fluctuation. Both the hit structures interacted strongly with the Asp180, Gln183, Gly184, Ser186, Gly207 and Gly209, as predicted by Glide XP docking, and formed a significant H-bond interaction with Ser181 in MD simulation. Among these two, ZINC000095912839 was having the most stable binding interaction with TMPRSS2 of the two molecules. The present study successfully identified TMPRSS2 ligands from a database of zinc natural molecules as potential leads for novel SARs-CoV-2 treatment. Supplementary Inform: The online version contains supplementary material available at 10.1007/s11224-022-01991-3.

Preliminary evaluation on the beneficial effects of pioglitazone in the treatment of endometrial cancer.

Endometrial cancer (EMC) is one of the complicated gynecological cancers, affecting more than three million women worldwide. Anticancer strategies such as chemotherapy, radiation, and surgery are found to be ineffective and are associated with patient incompliances. The aim of the present study is to repurpose non-oncological drug, i.e., Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, in the treatment of endometrial cancer. The study groups consist of 50 female Swiss albino mice, out of which 40 had endometrial cancer induced with N-ethyl-N-nitrosourea (ENU) and estradiol hexadrobenzoate (EHB). The other groups received saline, EHB, paclitaxel, and different test doses of pioglitazones. Different preliminary parameters such as weekly body weight, mean survival time, percentage increase in life span, and uterine tissue weight were analyzed along with histopathological analysis. We observed a significant change in weekly body weight, improvement in percentage life span, and partial restoration of uterine tissue weight to normal compared to a standard drug, paclitaxel. In the present preliminary evaluation, we have identified that pioglitazone exhibited a significant dose-dependent anticancer activity against ENU- and EHB-induced endometrial cancer, compared to the standard paclitaxel.