Induction of Caspase-Mediated Apoptosis in HepG2 Liver Carcinoma Cells Using Mutagen–Antioxidant Conjugated Self-Assembled Novel Carbazole Nanoparticles and In Silico Modeling Studies

In this study, novel self-assembled carbazole-thiooctanoic acid nanoparticles (CTNs) were synthesized from amino carbazole (a mutagen) and thiooctanoic acid (an antioxidant). The nanoparticles were characterized using hyperspectral techniques. Then, the antiproliferative potential of CTNs was determined in HepG2 liver carcinoma cells. This study employed a solvent-antisolvent interaction method to synthesize a spherical CTN of size less than 50 nm. Moreover, CT was subsequently capped to gold nanoparticles (AuNPs) in the additional comparative studies. The CT derivative was synthesized from carbazole and lipoic acid by the amide bond formation reaction using a coupling agent. Furthermore, it was characterized using infrared (IR), 1H nuclear magnetic resonance, dynamic light scattering (DLS), and transmission electron microscopy techniques. The CT-capped gold nanoparticles (CTAuNPs) were prepared from CT, chloroauric acid, and NaBH4. The CTAuNPs were characterized using ultraviolet-visible, high-resolution TEM, DLS, and Fourier transform IR techniques. The cytotoxicity and apoptosis-inducing ability of both nanoparticles were determined in HepG2 cells. The results demonstrate that CTNs exhibit antiproliferative activity in the cancerous HepG2 cells. Moreover, molecular docking and molecular dynamics studies were conducted to explore the therapeutic potential of CT against human EGFR suppressor protein to gain more insights into the binding mode of the CT, which may show a significant role in anticancer therapy

Evaluation of Rapanone and Nectandrin B as novel inhibitors for targeting the metastatic regulator protein BACH1 using breast cancer cell line Mcf-7

Cancer formation is defined as the unrestrained proliferation of cells due to various factors acting as a causing agent. A limited number of over-expressed transcription factors are contributed to the development of numerous types of cancer. The metastatic regulator protein BTB And CNC Homology 1 (BACH1) is Cap ‘N’ Collar (CNC) and it belongs to a basic region leucine zipper (bZIP) family. The presence of the least level concentration of intracellular heme BACH1 forms heterodimers with musculo aponeurotic fibrosarcoma (sMAF) proteins and inhibits or induces the target gene expression. Based on the previous studies, BACH1 plays a critical player in the conditions of senescence and oxidative stress, cycling of cell life, heme degradation pathway and cancer, especially in metastasis. Discovering new anti-cancer drugs (identification of bioactive compounds) stages finally needs to inhibit the target protein. This present study is aimed to screen and identify stability, binding affinity and analysis of pharmacokinetics of selected compounds through structural screening, ADMET, DFT and MESP. From this study, it is revealed that Rapanone and Nectandrin B have the potential to alter the degree of gene expression via binding with the BACH1 allosteric region which will further change the degree of expression of BACH1 downstream target genes involved in the regulation of cancer progression particularly in metastasis. The two plant origin compounds Rapanone and Nectandrin B might be novel candidates for developing anti-cancer drugs. The predicted compounds were further validated through in-vitro experimental approaches. Communicated by Ramaswamy H. Sarma.</p

Benchmarking docking, density functional theory and molecular dynamics studies to assess the aldose reductase inhibitory potential of Trigonella foenum-graecum compounds for managing diabetes-associated complications

Inhibition of aldose reductase (AR) could be a beneficial strategy for managing diabetes-associated complications. Trigonella foenum-graecum (TFG) is used around the globe as a traditional medicine for the management of diabetes. Our study aimed to assess the potential of TFG phytocompounds as inhibitors of AR in the context of diabetes-related complications. Our research work employed molecular docking, density functional theory (DFT) and molecular dynamics (MD) to evaluate the efficacy of TFG compounds. The study compared the predictive power of AutoDock and AutoDock Vina docking software and found that AutoDock Vina performs better in ranking and discriminating actives and decoys. The research identified five compounds as potential AR inhibitors from fifty-eight reported TFG phytoconstituents. Tigogenin and Gitogenin stood out as the most promising AR inhibitors. The electronic properties of the compounds were analysed through DFT studies and provided insights into their binding potential. Finally, the results of MD simulations indicated that Tigogenin and Gitogenin bound robustly with AR throughout the simulation period. This study predicted the AR inhibitory potential of TFG compounds for managing diabetes-associated complications and supports further drug development from TFG. The benchmarking approach used in this study improves the accuracy and dependability of bioactivity prediction

Benchmarking docking, density functional theory and molecular dynamics studies to assess the aldose reductase inhibitory potential of Trigonella foenum-graecum compounds for managing diabetes-associated complications

Inhibition of aldose reductase (AR) could be a beneficial strategy for managing diabetes-associated complications. Trigonella foenum-graecum (TFG) is used around the globe as a traditional medicine for the management of diabetes. Our study aimed to assess the potential of TFG phytocompounds as inhibitors of AR in the context of diabetes-related complications. Our research work employed molecular docking, density functional theory (DFT) and molecular dynamics (MD) to evaluate the efficacy of TFG compounds. The study compared the predictive power of AutoDock and AutoDock Vina docking software and found that AutoDock Vina performs better in ranking and discriminating actives and decoys. The research identified five compounds as potential AR inhibitors from fifty-eight reported TFG phytoconstituents. Tigogenin and Gitogenin stood out as the most promising AR inhibitors. The electronic properties of the compounds were analysed through DFT studies and provided insights into their binding potential. Finally, the results of MD simulations indicated that Tigogenin and Gitogenin bound robustly with AR throughout the simulation period. This study predicted the AR inhibitory potential of TFG compounds for managing diabetes-associated complications and supports further drug development from TFG. The benchmarking approach used in this study improves the accuracy and dependability of bioactivity prediction

Combination of bendamustine-azacitidine against Syk target of breast cancer: an <i>in silico</i> study

Breast cancer (BC) is the most serious and second leading cause of death in women worldwide. When breast cancer is diagnosed and treated early, the chance of long-term survival is up to 90%. On the other hand, 90% of BC patient deaths are due to metastasis and a lack of effective early diagnosis. The existing conventional chemotherapy provides negative feedback due to transportation barriers towards the action sites, multidrug resistance, poor bio-availability, non-specific delivery and systemic side effects on the healthy tissue. Syk protein Kinase has been reported in BC, as a tumor modulator, providing a pro-survival signal and also by restricting epithelial-mesenchymal transition, enhancing cell-cell interactions and inhibiting migration. In the present study, we explored the possibility of targeting BC by attenuating Syk protein Kinase. Hence, we have conjugated the hydrophobic Bendamustine (BEN) and hydrophilic Azacitidine (AZA) anticancer drugs to evaluate their efficacy against BC. The native drugs (BEN and AZA) and designed drug-drug conjugate (BEN-AZA) were docked with Syk protein. Then, the docked complex was performed for Binding Free Energy and Molecular Dynamics Simulations. Furthermore, DFT and ADME properties were carried out. The results revealed that the designed drug-drug conjugate has a better docking score, ΔGbind and admirable stability throughout the simulation when compared with native drugs. In DFT and ADME analyses, the designed drug-drug conjugate has shown good stereo electronic features and pharmaceutical relevant parameters than that of native drugs. The overall results suggested that the designed drug-drug conjugate may be a suitable candidate for BC treatment. Communicated by Ramaswamy H. Sarma</p