RESUMEN
Myeloid Cell Leukemia 1 (MCL1) is an anti-apoptotic protein that plays a critical role in regulating cell survival, particularly in cancer cells. It is a member of the BCL-2 family of proteins, which control the intrinsic pathway of apoptosis. MCL1 has emerged as a promising target for cancer therapy because it is overexpressed in a wide range of cancers, including breast, lung, prostate, and hematologic malignancies. Due to its remarkable role in cancer progression, it has been reflected as a promising drug target for cancer therapy. A few MCL1 inhibitors have been identified previously, but further research is needed to develop novel, effective and safe MCL1 inhibitors that can overcome resistance mechanisms and minimize toxicity in normal cells. In this study, we aim to search for compounds that target the critical binding site of MCL1 from phytoconstituent library from the IMPPAT database. To accomplish this, a multitier virtual screening approach involving molecular docking and molecular dynamics simulations (MDS) were used to evaluate their suitability for the receptor. Notably, certain screened phytoconstituents have appreciable docking scores and stable interactions toward the binding pocket of MCL1. The screened compounds underwent ADMET and bioactivity analysis to establish their anticancer properties. One phytoconstituent, Isopongaflavone, was identified that exhibiting higher docking and drug-likeness than the already reported MCL1 inhibitor, Tapotoclax. Isopongaflavone and and Tapotoclax, along with MCL1, were subjected to 100 nanoseconds (ns) MDS study to verify their stability inside the binding site of MCL1. The MDS findings demonstrated a strong binding affinity between Isopongaflavone and the MCL1 binding pocket, resulting in reduced conformational fluctuations. This investigation proposes Isopongaflavone as a promising candidate for the development of innovative anticancer therapeutics, pending the necessary validation procedures. Also, the findings provide valuable information for designing MCL1 inhibitors based on the protein's structure.Communicated by Ramaswamy H. Sarma.
RESUMEN
CDK6 is a critical protein involved in the regulation of the cell cycle, playing an important role in the progression from the G1 to S phase. In breast cancer, dysregulation of this protein is involved in tumour development and progression, particularly in hormone receptor-positive (HR+) breast cancers. The upregulation of CDK6 have been observed in a subset of breast cancers, leading to uncontrolled progression of the cell cycle and increased proliferation of cells. The purpose of this abstract is to provide an outline of CDK6's role. In breast cancer and the therapeutic strategies targeting CDK6 using specific selected inhibitors. To discover viable therapeutic candidates after competitive inhibition of CDK6 with a small molecular drug complex, high throughput screening and docking studies were used. Further, we carried the compounds based on ADMET properties and prediction of activity spectra for substances analysis. Finally, two different compounds were selected to carry out MD simulations. CDK6-IMPHY002642 and CDK6-IMPHY005260 are the two compounds that were identified. Overall, our results suggest that the CDK6-IMPHY002642 and CDK6-IMPHY005260 complex was relatively stable during the simulation. The compounds that have been found can also be further examined as potential therapeutic possibilities. The combined findings suggest that CDK6, together with their genetic changes, can be investigated in therapeutic interventions for precision oncology, leveraging early diagnostics and target-driven therapy.Communicated by Ramaswamy H. Sarma.
RESUMEN
Lung cancer detection includes detection of a pattern formed by multiple volatile organic compounds. An individual material has limited selectivity and hence requires tailoring to improve the selectivity and sensing properties. An electronic nose (e-nose) is a concept/device that can help in achieving selectivity and specificity for multiple volatile organic compounds at the same time by using an array of sensors. In this paper, Co and Ni doping in tin oxide was used to investigate as a sensor material for e-nose development. These were synthesized using a sol-gel method and were characterized for structural, morphological, and elemental assessment using X-ray diffraction, field emission scanning electron microscopy, and Fourier transform infrared spectroscopy, which indicated the formation of the composite nanomaterial of SnO2. These synthesized materials were then used as a working electrode in the form of a screen-printed electrode to determine 1-propanol and isopropyl alcohol (IPA) sensing characteristics. Electrochemical characterization was done by cyclic voltammetry (CV) and electrochemical impedance spectroscopy. In the case of CV studies, well-defined and distinct redox peaks are observed at different potential values indicating the changes due to the dopants. Ni doping in SnO2 shows the highest sensitivity of 2.99 µA/ppb for isopropyl alcohol and 3.11 for 1-propanol, within the detection range. Furthermore, Co-SnO2 shows selectivity for IPA, while Ni-SnO2 is selective to 1-propanol against all other volatile compounds analyzed.