RESUMO
The BRAF gene is responsible for transferring signals from outside of the cell to inside of the nucleus by converting a protein namely B-Raf through the RAS/MAPK pathway. This pathway contribute to cell division, proliferation, migration, and apoptotic cell death of human and animal. Mutation in this gene may cause the development of several cancers, including lung, skin, colon, and neuroblastoma. Currently, a few available drugs are being used that has developed by targeting the BRAF mutated protein, and due to the toxic side effects, patients suffer a lot during their treatment. Therefore this study aimed to identify potentially lead compounds that can target and block the expression of BRAF and subsequently inhibit the cancer. The hits were generated through the pharmacophore model-based virtual screening, molecular docking, pharmacohore model validation, ADME (absorption, distribution, metabolism, and excretion) analysis molecular dynamics (MD) simulation to find more suitable candidate against the overexpress BRAF gene. The pharmacophore based screening initially identified 14 k possible hits from online database which were further screened by ligand scout advance software to get hit compound. Based on molecular docking score of ZINC70454679 (-10.6 kcal/mol), ZINC253500968 (-9.4 kcal/mol), ZINC106887736 (-8.6 kcal/mol), and ZINC107434492 (-8.1 kcal/mol), pharmacophore feature and toxicity evaluation, we selected four possible lead compounds. The dynamic simulation with Schrodinger Maestro software was used to determine the stability of the potential lead candidates with target protein (PDB ID: 5VAM). The results showed that the newly obtained four compounds were more stable than the control ligand (Pub Chem ID: 90408826). The current results showed that the ZINC70454679, ZINC253500968, ZINC106887736, and ZINC107434492 compounds may be able to work against several cancers through targeting the BRAF overexpressed gene. To develop a novel drug candidate, however the evaluation of the web lab based experimental work are necessary to evaluate the efficiency of the each compound against the BRAF target gene.
RESUMO
Minichromosome maintenance protein 2 (MCM2) is a highly conserved protein from the MCM protein family that plays an important role in eukaryotic DNA replication as well as in cell cycle progression. In addition, it maintains the ploidy level consistency in eukaryotic cells, hence, mutations or alteration of this protein could result in the disintegration of the fine-tuned molecular machinery that can lead to uncontrolled cell proliferation. Moreover, MCM2 has been found to be an important marker for progression and prognosis in different cancers. Therefore, we aimed to analyze the MCM2 expression and the associated outcome in breast cancer (BC) patients based on the publicly available online databases. In this study, server-based gene expression analyses indicate the upregulation of MCM2 (p < 10-6; fold change>2.0) in various BC subtypes as compared to the respective normal tissues. Besides, the evaluation of histological sections from healthy and cancer tissues showed strong staining signals indicating higher expression of MCM2 protein. The overexpression of MCM2 was significantly correlated to promoter methylation and was related to patients' clinical features. Further, mutation analysis suggested missense as the predominant type of mutation (71.4%) with 18 copy-number alterations and 0.2% mutation frequency in the MCM2 gene. This study revealed a significant correlation (Cox p ≤ 0.05) between the higher MCM2 expression and lower patient survival. Finally, we identified the co-expressed genes with gene ontological features and signaling pathways associated in BC development. We believe that this study will provide a basis for MCM2 to be a significant biomarker for human BC prognosis.