ARID1A, a key subunit of the SWI/SNF chromatin remodeling complex, plays a context-dependent function in cancer, acting both as a tumor suppressor and, in certain conditions, as an oncogene. ARID1A, as a tumor suppressor, maintains transcriptional regulation, genomic stability, and cellular differentiation. In breast cancer, ARID1A loss-of-function leads to dysregulation of cell cycle checkpoints and impaired DNA repair and promotes epithelial-to-mesenchymal transition (EMT), jointly accelerating tumor proliferation and increasing therapeutic resistance. Notably, context-dependent ARID1A loss-of-function often concurs with activation of the PI3K/AKT signaling pathway and corresponds with poor prognosis. On the contrary, aberrant ARID1A overexpression can provoke oxidative stress and agitate the cytochrome P450 system, potentially facilitating early tumorigenesis. Consequently, understanding ARID1A’s dual and context-dependent role highlights its potential as a biomarker and therapeutic target in precision oncology.

Chandipura virus (CHPV) is a vesiculovirus that is a member of Rhabdviridae and is an encephalitic pathogen responsible for numerous epidemics in Central and Western India. The virus affects the brain and central nervous system mainly in children under 15 age of years, leading to neurological dysfunctions. Vectors that include sand flies, mosquitoes, and ticks are the main culprits in the transmission of CHPV. Five structural proteins (N, P, M, G, and L) encode the viral genome. The nucleocapsid protein N (N protein) encapsulates the viral genomic RNA in an RNase-resistant state, which plays a crucial role in the viral life cycle. Currently, no effective vaccine or therapeutics are available to treat the viral infection, and therefore efficient interventions are urgently needed. The repurposing of drugs is one of the best possible ways to controlCHPV infections in India and other parts of the world. In this study, we used a structure-based virtual screening approach by using FDA-approved drugs against the nucleocapsid protein of CHPV. The docking process identified a few drug candidates, which showed potent binding affinity towards the N protein. We used the Schrödinger Desmond v3.0 module; to compute the relative binding energies of ligands, we used the premier mm-GBSA module. Based on a short molecular dynamics simulation and prime MM-GBSA analysis, we identified Adrabetadex, Hydroxypropyl betadex, Beta-1,2,3,4,6-penta-O-Galloyl-D-Glucopyranose, thio-maltohexaose, and Indium-III pentetreotide as potent drug candidates for CHPV. Our computational results provide suggestions for in vitro and in vivo testing of these drugs against CHPV.

Introduction: The tryptophan (TRP)-serotonin pathway is disrupted and redirected towards kynurenine by the action of indoleamine 2,3-dioxygenase 2 (IDO2) and kynureninase (KYNU). In ovarian cancer, concurrent kynurenine activation encourages tumor growth and immune evasion. The investigation of phytochemicals has focused on identifying therapeutic targets in ovarian cancer. Methods: Gene expression, survival plots, and comparisons of correlated genes were computed to obtain holistic insights into the identified targets. A Kaplan-Meier analysis was performed to examine the survival patterns of IDO1 and KYNU targets. Molecular docking was performed to determine the binding affinity of ligands, and the Desmond module of Schrodinger was used to confirm the docking scores through simulation. Physiochemical and ADMET properties were assessed using SwissADME and pkCSM. Electronic effects and stability were further confirmed using Gaussian software. Results: Protein-protein interactions of TRP metabolism revealed IDO2 and KYNU as potential targets involved in pathway diversion. The comparison of mutated and non-mutated targets showed no significant difference, reflecting the tumor’s heterogeneity and the limited number of mutated samples. Molecular docking studies of 368 phytochemicals from six sources, reported to have anti-ovarian cancer properties, revealed 11 phytochemicals with higher binding affinities of -9.7 kcal/mol for IDO2 and -9.4 kcal/mol for KYNU. The interaction between the target and ligand was confirmed by molecular dynamics simulation using the Desmond module V3 of Schrödinger software. The stability and reactivity of phytochemicals were assessed using HOMO-LUMO and energy gap calculations. The highest electron stability was shown in 24MC (6.95 eV) and C24β (6.93 eV) compared with controls. The identified phytochemicals were further evaluated for their ADMET properties to refine therapeutic hit compounds. Compounds, such as Hemanthidine (HAT), Ergometrine (ERG), Tazettine (TZT), Tenatoprazole (TU-199), Rucaparib (CO-338), and Nicotinylalanine (NAL), have been reported to improve drug absorption. Discussion: By altering the ovarian cancer microenvironment, targeting immunometabolism with a clinically relevant approach improves therapeutic efficacy. Target expression clarifies the immune-rich tumor microenvironment rather than the actual tumor growth. Higher-binding- affinity compounds demonstrate high electronic stability in energy estimates as well as improved drug availability in pharmacokinetic investigations. However, this finding remains a computational approach and requires experimental validation. Discussion: By altering the ovarian cancer microenvironment, targeting immunometabolism with a clinically relevant approach improves therapeutic efficacy. Target expression clarifies the immune-rich tumor microenvironment rather than the actual tumor growth. Higher-binding-affinity compounds demonstrate high electronic stability in energy estimates as well as improved drug availability in pharmacokinetic investigations. However, this finding remains a computational approach and requires experimental validation. Conclusion: This computational study identifies suitable hit compounds for targeting TRP depletion, expanding the scope for subsequent in vitro and in vivo exploration to expedite drug discovery.