Identification of Novel EGFR Inhibitors for the Targeted Therapy of Colorectal Cancer Using Pharmacophore Modelling, Docking, Molecular Dynamic Simulation and Biological Activity Prediction.

BACKGROUND: Colorectal cancer (CRC) is considered the second deadliest cancer in the world. One of the reasons for the occurrence of this cancer is the deregulation of the Epidermal Growth Factor Receptor (EGFR), which plays a critical role in regulating cell division, persistence, differentiation, and migration. The overexpression of the EGFR protein leads to its dysregulation and causes CRC. OBJECTIVES: Hence, this work aims to identify and validate novel EGFR inhibitors for the treatment of colorectal cancer employing various computer aided techniques such as pharmacophore modeling, docking, molecular dynamic simulation and Quantitative Structure-Activity Relationship (QSAR) analysis. METHODS: In this work, a shared-featured ligand-based pharmacophore model was generated using the known inhibitors of EGFR. The best model was validated and screened against ZincPharmer and Maybridge databases, and 143 hits were obtained. Pharmacokinetic and toxicological properties of these hits were studied, and the acceptable ligands were docked against EGFR. The best five protein-ligand complexes with binding energy less than -5 kcal/mol were selected. The molecular dynamic simulation studies of these complexes were conducted for 100 nanoseconds (ns), and the results were analyzed. The biological activity of this ligand was calculated using QSAR analysis. RESULTS: The best complex with Root Mean Square Deviation (RMSD) 3.429 Å and Radius of Gyration (RoG) 20.181 Å was selected. The Root Mean Square Fluctuations (RMSF) results were also found to be satisfactory. The biological activity of this ligand was found to be 1.38 µM. CONCLUSION: This work hereby proposes the ligand 2-((1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)oxy)-N- (1H-indol-4-yl)acetamide as a potential EGFR inhibitor for the treatment of colorectal cancer. The wet lab analysis must be conducted, however, to confirm this hypothesis.

UBA52 Attunes VDAC1-Mediated Mitochondrial Dysfunction and Dopaminergic Neuronal Death.

Mitochondrial homeostasis regulates energy metabolism, calcium buffering, cell function, and apoptosis. The present study has been conducted to investigate the implications of the ubiquitin-encoding gene UBA52 in mitochondrial physiology. Transient expression of Myc-UBA52 in neurons significantly inhibited the rotenone-induced increase in reactive oxygen species generation, nitrite level, and depleted glutathione level. Mass spectrometric and coimmunoprecipitation data suggested the profound interaction of UBA52 with mitochondrial outer membrane channel protein, VDAC1 in both the wild-type and Myc-α-synuclein overexpressed neuronal cells and in the Parkinson's disease (PD)-specific substantia nigra and striatal region of the rat brain. In vitro ubiquitylation assay revealed that UBA52 participates in the ubiquitylation of VDAC1 through E3 ligase CHIP. Myc-UBA52 overexpression in neurons further improved the mitochondrial functionality and cell viability by preventing the alteration in mitochondrial membrane potential, mitochondrial complex I activity, and translocation of cytochrome c and p-Nrf2 along with the effect on intracellular calcium uptake, thus collectively inhibiting the opening of mitochondrial permeability transition pore. Additionally, Myc-UBA52 expression in neuronal cells offered protection against apoptotic and autophagic cell death. Altogether, our findings delineate a functional association between UBA52 and mitochondrial homeostasis, providing new insights into the deterrence of dopaminergic cell death during acute PD pathogenesis.

A Rare Case of Glial Choristoma Arising from the Vomer in Association with Cleft Palate.

Heterotopic neuroglial tissue represents normal glial tissue in an abnormal location distant from the central nervous system. It is a rare congenital condition and the majority of these lesions are diagnosed at birth or early childhood. We report a rare case scenario of a growth arising from the vomer associated with cleft palate. The origin of a glial choristoma from the midline of the nasal cavity in association with a cleft palate has not been reported in the literature. Complete surgical excision was performed prior to palatoplasty with no postoperative complications or evidence of recurrence.

Implications of intracellular protein degradation pathways in Parkinson's disease and therapeutics.

Parkinson's disease (PD) pathology is the most common motor neurodegenerative disease that occurs due to the progressive degeneration of dopaminergic neurons of the nigrostriatal pathway of the brain. The histopathological hallmark of the disease is fibrillary aggregate called Lewy bodies which majorly contain α-synuclein, suggesting the critical implication of diminished protein degradation mechanisms in disease pathogenesis. This α-synuclein-containing Lewy bodies are evident in both experimental models as well as in postmortem PD brain and are speculated to be pathogenic but still, the lineal association between these aggregates and the complexity of disease pathology is not yet well established and needs further attention. However, it has been reported that α-synuclein aggregates have consorted with the declined proteasome and lysosome activities. Therefore, in this review, we reappraise intracellular protein degradation mechanisms during PD pathology. This article focused on the findings of the last two decades suggesting the implications of protein degradation mechanisms in disease pathogenesis and based on shreds of evidence, some of the approaches are also suggested which may be adopted to find out the novel therapeutic targets for the management of PD patients.

Electron spin relaxation time of Ni(II) ion in hexapyrazole zinc(II) dinitrate at 300 K.

Understanding the electron spin relaxation properties of paramagnetic species is a fundamental requirement to use them as a probe to measure distances between sites in biomolecules by electron paramagnetic resonance (EPR) spectroscopy. Even though Ni(II) ion is an essential trace element for many species, relaxation properties are not well understood. Herein, the polycrystalline sample of Ni(II) ion magnetically diluted in Zn(Pyrazole)6 (NO3 )2 (Ni/ZPN) has been studied in detail by EPR spectroscopy to explore the electron spin relaxation time. Progressive continuous-wave (CW) EPR power saturation study on Ni/ZPN at 300 K yielded 907 mW as the P1/2 value. The cavity constant (KQ ) has been calculated using tempol in PVA-BA glass matrix and the product of electron spin-lattice relaxation time (T1 ) and spin-spin relaxation time (T2 ) for Ni/ZPN at 300 K has been reported for the first time.