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Background: Pancreatic cancer metastasis is characterized by a higher incidence of morbidity and mortality. The present study attempts to identify phytocomponents with the potential to inhibit the secretion of MMP-2 by pancreatic cancer cells and ascertain the efficacy of individual components. Methods: Overall survival analysis carried out revealed reduced survival of patients with high MMP-2 expression. Data analysis from TCGA revealed increased MMP-2 expression in pancreatic cancer patients compared to adjacent normal tissues. The expression of MMP-2 was reported at different stages of pancreatic cancer (Stage I-IV). To understand the relevance of phytocomponents in binding to the catalytic site of MMP-2, molecular docking studies were performed to find the effectiveness based on Glide score/energy. To substantiate the in-silico analysis, the eight components were also tested in vitro for reducing the survival in PANC-1 cells at three different time points (24, 48, and 72 hours). Finally, zymography analysis was performed using the eight components in the PANC-1 conditioned media of treated cells to ascertain the enzymatic activity of MMP-2. Results: The obtained results suggest plumbagin, emodin, and EGCG exert potential inhibition in PANC-1 cells, among other phytocomponents tested. Therefore, as assessed using computational studies, the binding ability of plumbagin, emodin, and EGCG can be interpreted as inhibiting effects on MMP-2 activities. Conclusion: These compounds could find potential application in preventing the progression, sustenance, and metastasis of pancreatic cancer and need to be explored further using a pre-clinical model system in order to validate the efficacy, bioavailability, and safety.

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides (MM-compounds) are a relatively new class of heterocyclic compounds that exhibit a wide variety of biological actions, including anticancer properties. Here, we used caspase enzyme activity assays, flow cytometry analysis of propidium iodide (PI)-stained cells, and a DNA laddering assay to investigate the mechanisms of cell death triggered by the MM-compounds (MM134, -6, -7, and -9). Due to inconsistent results in caspase activity assays, we have performed a bromodeoxyuridine (BrdU) incorporation assay, colony formation assay, and gene expression profiling. The compounds’ cytotoxic and pro-oxidative properties were also assessed. Additionally, computational studies were performed to demonstrate the potential of the scaffold for future drug discovery endeavors. MM-compounds exhibited strong micromolar (0.06–0.35 µM) anti-proliferative and pro-oxidative activity in two cancer cell lines (BxPC-3 and PC-3). Activation of caspase 3/7 was observed following a 24-h treatment of BxPC-3 cells with IC50 concentrations of MM134, -6, and -9 compounds. However, no DNA fragmentation characteristics for apoptosis were observed in the flow cytometry and DNA laddering analysis. Gene expression data indicated up-regulation of BCL10, GADD45A, RIPK2, TNF, TNFRSF10B, and TNFRSF1A (TNF-R1) following treatment of cells with the MM134 compound. Moreover, in silico studies indicated AKT2 kinase as the primary target of compounds. MM-compounds exhibit strong cytotoxic activity with pro-oxidative, pro-apoptotic, and possibly pro-necroptotic properties that could be employed for further drug discovery approaches.

Lymphatic filariasis is a parasitic disease caused by the worms Wuchereria bancrofti, Brugia malayi and Brugia timori. Three anti-filarial drugs namely Diethylcarbamazine, Ivermectin and Albendazole and their combinations are used as the control strategies for filariasis. The disease has received much attention in drug discovery due to the unavailability of vaccines and the toxic pharmaceutical properties of the existing drugs. In Wolbachia endosymbiont Brugia malayi, the UDP-N-acetylmuramoyl-tripeptide-d-alanyl-d-alanine ligase (MurF) plays a key role in peptidoglycan biosynthesis pathway and therefore can be considered as effective drug target against filariasis disease. Therefore, in the present study, MurF was selected as the therapeutic target to identify specific inhibitors against filariasis. Homology modeling was performed to predict the three-dimensional structure of MurF due to the absence of the experimental structure. Further molecular dynamics simulation and structure-based high throughput virtual screening with three different chemical databases (Zinc, Maybridge and Specs) were carried out to identify potent inhibitors and also to check their conformations inside the binding site of MurF, respectively. Top three compounds with high docking score and high relative binding affinity against MurF were selected. Further, validation studies, including predicted ADME (Absorption, Distribution, Metabolism, Excretion) assessment, binding free energy using MM-GBSA (Molecular Mechanics Generalized Born Surface Area) and DFT (Density Functional Theory) calculations were performed for the top three compounds. From the results, it was observed that all the three compounds were predicted to show high reactivity, acceptable range of pharmacokinetic properties and high binding affinity with the drug target MurF. Overall, the results could provide more understanding on the inhibition of MurF enzyme and the screened compounds could lead to the development of new specific anti-filarial drugs.