Levetiracetam is an effective antiseizure medication whose use is frequently limited by neuropsychiatric adverse effects, including irritability, agitation, aggression, and less commonly psychosis and mood disturbance. These reactions are not readily explained by its established action at synaptic vesicle glycoprotein 2A (SV2A), raising the possibility of off-target activity at monoaminergic receptors. We hypothesised that the racetams engage the dopamine D₂ and serotonin 5-HT₂A receptors, and that the pattern of engagement parallels the distinct clinical liabilities of individual racetams. Levetiracetam, brivaracetam and piracetam were docked into the orthosteric pockets of both receptors and simulated in an explicit lipid bilayer as three independent 50 ns replicates per system, branched from identical equilibrated coordinates with independently seeded velocities (18 trajectories in total). Pose persistence was robust: in every frame of every trajectory the minimum ligand–receptor heavy-atom distance remained at or below 4.0 Å, and no ligand dissociated. Per-residue contact profiles, however, varied substantially between replicates of the same system. Contact with the orthosteric anchor aspartate ranged from 85 to 13
Acetylcholinesterase (AChE) remains one of the important targets for treating patients with Alzheimer’s disease (AD). Currently there are no complete treatments available for the disease. This study is aimed to virtually identify novel cis-hydroxycinnamic acid with potential to inhibit AChE enzyme. A series of 21 alkyl/aryl derivatives of cis-o-hydroxycinnamic acid was hypothesized. The compounds were subjected to molecular docking using Auto Dock tools to find the binding interactions of the compounds with the target protein, acetylcholinesterase. About 14 compounds displayed predicted binding affinity ranging from − 9.83 to − 13.88 kcal/mol in comparison to standard Donepezil displaying ΔG of − 11.46 kcal/mol. Swiss ADME and Deep PK deduced their drug likeness and ADMET profile. The results of binding interactions were validated through DFT calculations using ORCA that helped to calculate various electronic parameters, frontier molecular orbitals and molecular electrostatic potential maps. Compounds 8, 9, 10, 11, 12, 13, 14 15, 16, 17, 18, 19, 20, 21 displayed appreciable binding interactions, majority of drug likeness parameters, optimal pharmacokinetic and electronic profile. However, the most balanced and favourable profile was observed for compounds 14 and 19 which demonstrated the need for evaluating the flexibility and structural rigidity of the docked complexes using Cabs-flex and IMODS. The docked complexes of both the compounds 14 and 19 revealed the optimal flexibility and physical movement. The findings in this study thus reveal that these derivatives of cis-o-hydroxycinnamic acid have the potential to act as promising acetylcholinesterase inhibitors. However, experimental studies need to be carried out to further validate this in silico study.
Lung adenocarcinoma (LUAD) is a major cause of cancer-related morbidity and mortality, highlighting the need for therapeutic strategies capable of targeting multiple oncogenic pathways. In this study, an integrative computational framework that combines pharmacokinetic profiling, protein interaction network analysis, molecular docking, 200 ns molecular dynamics (MD) simulations, MM-GBSA binding free-energy estimation, transcriptomic analysis, genomic alteration assessment, and consensus miRNA modeling was used to explore curcumin and resveratrol as potential modulators of the molecular processes associated with MMP9 and SIRT1 in LUAD. Both compounds exhibited favorable drug-likeness characteristics, gastrointestinal absorption, and predicted low acute toxicity. Network analysis identified MMP9- and SIRT1-centered interaction networks with TP53 emerging as a common central node. Molecular docking predicted favorable interactions of curcumin with MMP9 and resveratrol with SIRT1. However, SIRT1 docking validation produced an RMSD of 2.26 Å, slightly exceeding the predefined 2.0 Å threshold; therefore, the resveratrol-SIRT1 docking result was considered supportive rather than fully validated structural evidence. The 200 ns MD simulations indicated satisfied conformational behavior of both protein-ligand complexes, supported by RMSD, hydrogen-bond, and other structural analyses. Further, MM-GBSA analysis provided complementary computational evidence for favorable binding energetics. The weak negative co-expression of both genes was observed in TCGA-LUAD analysis (P < 0.05), and they also had significant tumor-associated upregulation. The functional enrichment analysis indicated that MMP9 and SIRT1 have different but complementary roles; MMP9 was enriched with genes involved in extracellular matrix remodeling, inflammation and proteolytic processes while SIRT1 was enriched with genes involved in metabolic, epigenetic and cellular stress response processes. Importantly, the present study does not establish pharmacological synergy between curcumin and resveratrol. Instead, the synthesized results offer a hypothesis-driven approach for exploring other mechanisms potentially involving MMP9 and SIRT1 and evaluating their synergistic benefits in LUAD when combined with these two natural compounds. Experimental biochemical, cellular, pharmacokinetic, toxicological, and in vivo studies are required to validate the predicted interactions and determine their biological and therapeutic relevance.
The Monoamine Oxidase-B (MAO-B) is a flavin adenine dinucleotides enzyme found in the brain, intestine liver, and placenta. Recently MAO-B has drawn important attention for neurodegenerative disease treatment. Firstly, the Smina-A fork of AutoDock Vina and idock tools were used for the screening of 98,072 compounds. Based on a binding cut-off of >= − 11.5 Kcal/mol, the potential inhibitors were selected and evaluated through the ADMET filters. The ADMET analysis revealed that 18 compounds were best in the pharmacokinetics descriptors evaluation hence we have used the cross-docking approach to confirm the virtual screening result for these 18 compounds. Cross-docking results revealed that four compounds showed a higher binding affinity and interaction with the key catalytic residues. Hence, we have taken these four hits and employed them for the MDS analysis. The MAO-B-RGZ, MAO-B-ZINC2147610, MAO-B-ZINC4237106, MAO-B-ZINC4701203 and MAO-B-ZINC5818772 showed − 67.45, − 103.75, − 88.39, − 96.27 and − 104.11 kJ/mol binding free energy. The overall result of docking, MDS, and binding free energy showed that all the predicted leads are favorable towards the MAO-B binding site. Therefore, we have proposed that ZINC2147610, ZINC4237106, ZINC4701203, and ZINC5818772 as potential hit compounds against MAO-B to open a new gate for the neurodegenerative disease treatment. However, experimental validation is necessary to confirm their biological activity, binding affinity, and therapeutic potential before they can be advanced as putative hits.
Intracellular redox homeostasis is crucial for cancer cell survival, making the antioxidant defense network an attractive target for therapeutic intervention. This study utilized an integrated in silico and in vitro approach to screen twenty-one oxidative stress-associated compounds against the crystal structures of glutathione peroxidase 4 (GPX4), glutathione reductase (GR), and thioredoxin reductase 1 (TrxR1) to identify potential multi-targeting pro-oxidant candidates. Our initial in silico molecular docking simulations and thermodynamic evaluations identified the kinase inhibitor Alectinib as a premier multi-targeting ligand, showing favourable docking scores and predicted dissociation constants (Kd) toward GR (1.52 × 10−7 M) and TrxR1 (5.87 × 10−7 M). Subsequent in vitro validation using human lung adenocarcinoma, A549 cells revealed that Alectinib reduced cell viability in a concentration-dependent manner, establishing a 24-h IC50 value of approximately 10 µM. Crucially, at this therapeutic concentration, Alectinib increased intracellular ROS levels by approximately 14-fold as observed via DCFH-DA fluorescence microscopy. Mechanistically, this pro-oxidant state was accompanied by decreased intracellular GSH levels by approximately 50
