Molecular Insights Into Di(2-Picolyl) Amine-Induced Cytotoxicity and Apoptosis in Human Kidney (HEK293) Cells.

Di(2-picolyl) amine (DPA) is a pyridine derivative known to chelate metal ions and thus has potential anticancer properties; however, its effect on normal cells remains unchartered necessitating further research. This study, therefore, investigated the mechanistic effects of DPA-induced cytotoxicity and apoptosis in the HEK293 cell line. Methods required that an half the maximum inhibition concentration (IC50) was derived using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Analyses aimed to assess oxidative stress, membrane damage, and DNA fragmentation by means of biochemical assays were performed. Luminometry analysis was carried out to understand the mechanism of apoptosis induction by determining the levels of adenosine triphosphate (ATP) and the activities of caspase-8, -9, and -3/7. Western blotting was used to ascertain the expression of apoptotic and stress-related proteins. An IC50 of 1,079 µM DPA was obtained. Antioxidant effect correlated with a minimum increase in reactive oxygen species induced lipid peroxidation. The increase in initiator caspase-8 and -9 and executioner caspase-3/7 activities by DPA-induced apoptosis albeit prompting a decline in the levels of ATP. Furthermore, DPA brought about the following consequences on HEK293 cells: markedly elevated tail lengths of the comets, poly (ADP-ribose) polymerase 1 cleavage, and apoptotic body formation observed in the late stages. The cytotoxic effects of DPA in HEK293 cells may be mediated by induction of apoptosis via the caspase-dependent mechanism.

Understanding the Hsp90 N-terminal Dynamics: Structural and Molecular Insights into the Therapeutic Activities of Anticancer Inhibitors Radicicol (RD) and Radicicol Derivative (NVP-YUA922).

Heat shock protein 90 (Hsp90) is a crucial component in carcinogenesis and serves as a molecular chaperone that facilitates protein maturation whilst protecting cells against temperature-induced stress. The function of Hsp90 is highly dependent on adenosine triphosphate (ATP) binding to the N-terminal domain of the protein. Thus, inhibition through displacement of ATP by means of competitive binding with a suitable organic molecule is considered an attractive topic in cancer research. Radicicol (RD) and its derivative, resorcinylic isoxazole amine NVP-AUY922 (NVP), have shown promising pharmacodynamics against Hsp90 activity. To date, the underlying binding mechanism of RD and NVP has not yet been investigated. In this study, we provide a comprehensive understanding of the binding mechanism of RD and NVP, from an atomistic perspective. Density functional theory (DFT) calculations enabled the analyses of the compounds' electronic properties and results obtained proved to be significant in which NVP was predicted to be more favorable with solvation free energy value of -23.3 kcal/mol and highest stability energy of 75.5 kcal/mol for a major atomic delocalization. Molecular dynamic (MD) analysis revealed NVP bound to Hsp90 (NT-NVP) is more stable in comparison to RD (NT-RD). The Hsp90 protein exhibited a greater binding affinity for NT-NVP (-49.4 ± 3.9 kcal/mol) relative to NT-RD (-28.9 ± 4.5 kcal/mol). The key residues influential in this interaction are Gly 97, Asp 93 and Thr 184. These findings provide valuable insights into the Hsp90 dynamics and will serve as a guide for the design of potent novel inhibitors for cancer treatment.

Exploring the impact of H5N1 neuraminidase (H274Y) mutation on Peramivir: a bio-computational study from a molecular perspective.

Communicated by Ramaswamy H. Sarma.

Impact of Pyridyl Moieties on the Inhibitory Properties of Prominent Acyclic Metal Chelators Against Metallo-ß-Lactamase-Producing Enterobacteriaceae: Investigating the Molecular Basis of Acyclic Metal Chelators' Activity.

Carbapenem-resistant Enterobacteriaceae (CREs)-mediated infections remain a huge public health concern. CREs produce enzymes such as metallo-ß-lactamases (MBLs), which inactivate ß-lactam antibiotics. Hence, developing efficient molecules capable of inhibiting these enzymes remains a way forward to overcoming this phenomenon. In this study, we demonstrate that pyridyl moieties favor the inhibitory activity of cyclic metal-chelating agents through in vitro screening, molecular modeling, and docking assays. Di-(2-picolyl) amine and tris-(2-picolyl) amine exhibited great efficacy against different types of MBLs and strong binding affinity for NDM-1, whereas 2-picolyl amine did not show activity at a concentration of 64 mg/L in combination with meropenem; it further showed the lowest binding affinity from computational molecular analysis, commensurating with the in vitro screening assays. The findings revealed that the pyridyl group plays a vital role in the inhibitory activity of the tested molecules against CREs and should be exploited as potential MBL inhibitors.