Ginkgo Biflavones Cause p53 Wild-Type Dependent Cell Death in a Transcription-Independent Manner of p53.

Ginkgo biloba, as a medicinal plant in both traditional and western medicine, emerged as a potential therapeutic agent for the management of a variety of diseases, but ginkgo biflavones (bilobetin, isoginkgetin, and ginkgetin) application in cancer therapy and underlying mechanisms of action remained elusive. In the present study, we identified ginkgo biflavones as potential p53 activators that could enhance p53 protein expression level by inhibiting MDM2 protein expression. At the same time, they induced cell death independent of p53 transcriptional activity. Moreover, ginkgetin was a standout among ginkgo biflavones that reduced the survival of HCT-116 cells by induction of apoptosis and G2/M phase arrest. Furthermore, ginkgo biflavones induced ROS generation significantly, which resulted in ferroptosis. Finally, we provide evidence that ginkgetin strengthened the antitumor effect of fluorouracil (5-FU) in the HCT-116 colon cancer xenograft model. To sum up, ginkgo biflavones represent a new class of p53 activator that depends on the p53 wild-type status and warrants further exploration as potential anticancer agents.

Design, synthesis and antibacterial activity evaluation of ebselen derivatives in NDM-1 producing bacteria.

New Delhi-ß-lactamase-1 (NDM-1) is a type of metal-ß-lactamase. NDM-1-expressing bacteria can spread rapidly across the globe via plasmid transfer, which greatly undermines the clinical efficacy of the carbapenem. Research on NDM-1 inhibitors has attracted extensive attention. However, there are currently no clinically available NDM-1 inhibitors. Our research group has reported that 1,2-benzisoselenazol-3(2H)-one derivatives as covalent NDM-1 inhibitors can restore the efficacy of meropenem (Mem) against NDM-1 producing strains. In this study, 22 compounds were designed and synthesized, which restored the Mem susceptibility of NDM-1-expressing Escherichia coli. and its minimum inhibitory concentration (MIC) was reduced by 2-16 times. Representative compound A4 showed significant synergistic antibacterial activity against NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE) isolates. The in vitro NDM-1 enzyme inhibitory activity test showed that the IC50 was 1.26 ± 0.37 µM, which had low cytotoxicity. When combined with meropenem, it showed good combined antibacterial activity. Electrospray ionization mass spectrometry (ESI-MS) analysis demonstrates that compound A4 covalently binds to NDM-1 enzyme. In summary, compound A4 is a potent NDM-1 covalent inhibitor and provides a potential lead compound for drug development in resistant bacteria.

Hydrogen bonding penalty used for virtual screening to discover potent inhibitors for Papain-Like cysteine proteases of SARS-CoV-2.

The Papain-Like proteases (PLpro) of SARS-CoV-2 play a crucial role in viral replication and the formation of nonstructural proteins. To find available inhibitors, the 3D structure of PLpro of SARS2 was obtained by homologous modelling, and we used this structure as a target to search for inhibitors through molecular docking and MM/GBSA binding free energy rescoring. A novel hydrogen bonding penalty was applied to the screening process, which meanwhile took desolvation into account. Finally, 61 compounds were acquired and 4 of them with IC50 at micromolar level tested in vitro enzyme activity assay, which includes clinical drugs tegaserod. Considering the importance of crystal water molecules, the 4 compounds were re-docked and considered bound waters in the active site as a part of PLpro. The binding modes of these 4 compounds were further explored with metadynamics simulations. The hits will provide a starting point for future key interactions identified and lead optimization targetting PLpro.