GC-MS analysis, pharmacokinetic properties, molecular docking and dynamics simulation of bioactives from Curcumis maderaspatanus to target oral cancer.

Oral cancer (OC) which is the most predominant malignant epithelial neoplasm in the oral cavity, is the 8th commonest type of cancer globally. Natural products are excellent sources of functionally active compounds and essential nutrients that play an important role in cancer therapeutics. Using the structure-based virtual screening, drug-likeness, toxicity, and molecular dynamics simulation, the current study focused on the evaluation of anticancer activity of bioactive compounds from Curcumis maderaspatanus. AURKA, CDK1, and VEGFR-2 proteins which play a crucial role in the development and progression of oral cancer was selected as targets and 216 phytochemicals along with a known reference inhibitor were docked against these target proteins. Based on the docking score, it was found that phytochemicals namely 3-Benzoyl-2,4(1H,3H)-Pyrimidinedione (- 8.0 kcal/mol), 1-Cyclohexylethanol, trifluoroacetate (- 6.3 kcal/mol), and Alpha-Curcumene (- 8.9 kcal/mol) interacts with AURKA, CDK1, and VEGFR-2 with highest binding affinity. The molecular dynamics simulation demonstrated that the best docked complexes exhibited excellent structural stability in terms of RMSD, RSMF, SASA and Rg for a period of 100 ns. Altogether, our computational analysis reveals that the bioactives from C. maderaspatanus could emerge as efficacious drug candidates in oral cancer therapy. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00177-x.

Interactions between HIV protease inhibitor ritonavir and human DNA repair enzyme ALKBH2: a molecular dynamics simulation study.

The human DNA repair enzyme AlkB homologue-2 (ALKBH2) repairs methyl adducts from genomic DNA. Overexpression of ALKBH2 has been implicated in both tumorigenesis and chemotherapy resistance in some cancers, including glioblastoma and renal cancer rendering it a potential therapeutic target and a diagnostic marker. However, no inhibitor is available against these important DNA repair proteins. Intending to repurpose a drug as an inhibitor of ALKBH2, we performed in silico evaluation of HIV protease inhibitors and identified Ritonavir as an ALKBH2-interacting molecule. Using molecular dynamics simulation, we elucidated the molecular details of Ritonavir-ALKBH2 interaction. The present work highlights that Ritonavir might be used to target the ALKBH2-mediated DNA alkylation repair.

Human RAD51 paralogue RAD51C fosters repair of alkylated DNA by interacting with the ALKBH3 demethylase.

The integrity of our DNA is challenged daily by a variety of chemicals that cause DNA base alkylation. DNA alkylation repair is an essential cellular defence mechanism to prevent the cytotoxicity or mutagenesis from DNA alkylating chemicals. Human oxidative demethylase ALKBH3 is a central component of alkylation repair, especially from single-stranded DNA. However, the molecular mechanism of ALKBH3-mediated damage recognition and repair is less understood. We report that ALKBH3 has a direct protein-protein interaction with human RAD51 paralogue RAD51C. We also provide evidence that RAD51C-ALKBH3 interaction stimulates ALKBH3-mediated repair of methyl-adduct located within 3'-tailed DNA, which serves as a substrate for the RAD51 recombinase. We further show that the lack of RAD51C-ALKBH3 interaction affects ALKBH3 function in vitro and in vivo. Our data provide a molecular mechanism underlying upstream events of alkyl adduct recognition and repair by ALKBH3.

Heteroexpression of Mycobacterium leprae hypothetical protein ML0190 provides protection against DNA-alkylating agent methyl methanesulfonate.

Repair of DNA alkylation damage is essential for maintaining genome integrity and Fe(II)/2-oxoglutarate(2OG)-dependent dioxygenase family of enzymes play crucial role in repairing some of the alkylation damages. Alkylation repair protein-B (AlkB) of Escherichia coli belongs to Fe(II)/2OG-dependent dioxygenase family and carries out DNA dealkylation repair. We report here identification of a hypothetical Mycobacterium leprae protein (accession no. ML0190) from the genomic database and show that this 615-bp open reading frame encodes a protein with sequence and structural similarity to Fe(II)/2OG-dependent dioxygenase AlkB. We identified mRNA transcript of this gene in the M. leprae infected clinical skin biopsy samples isolated from the leprosy patients. Heterologous expression of ML0190 in methyl methane sulfonate (MMS) sensitive and DNA repair deficient strain of Saccharomyces cerevisiae and Escherichia coli resulted in resistance to alkylating agent MM. The results of the present study imply that Mycobacterium leprae ML0190 is involved in protecting the bacterial genome from DNA alkylation damage.

New biomarkers in brain trauma.

Brain-specific biomolecules are being increasingly investigated as a viable alternative to the clinical scores and radiological features, on which we still rely upon for stratification, therapy and predicting outcome in traumatic brain injury (TBI). TBI generally leads to release of various chemical compound within the cerebrospinal fluid (CSF) or blood depending on the severity of injury, which were studied variedly in last decades. However, most of these compounds being non-specific to brain, their applicability was challenged further. This review encompasses the novel and promising biomarkers being studied in the present decade, with encouraging results in laboratory and animal or human models.