Rheumatoid arthritis (RA) is a chronic autoimmune disorder that causes joint pain and inflammation. Despite the availability of various treatments, their side effects often limit their long-term effectiveness, leading to increased interest in natural compounds with fewer adverse effects. Nigella sativa (black cumin), known for its diverse pharmacological properties, including anti-inflammatory effects, has gained attention as a potential treatment for RA. However, the specific pharmacological actions of black cumin seed oil in treating arthritis are not well-established. In this context, the current study aimed to evaluate the therapeutic potential of black seed oil by various computational studies like ADMET prediction, network pharmacology, molecular docking, and molecular dynamics simulations. Based on the network pharmacology results, the identified top 2 targets (IL6 and STAT3) are further screened for molecular docking studies with PDB IDs 1alu and 6NJS, respectively. The docking results revealed that eicosadienoic acid exhibited stronger binding activity than the standard methotrexate against the protein ID 1ALU and 6NJS, with docking scores of -7.82 and -8.66 kcal/mol, respectively. Molecular dynamics simulations showed that the eicosadienoic acid IL6 complex remained stable between 40 and 85 nanoseconds. These findings revealed that eicosadienoic acid is a promising therapeutic agent for targeting RA.
Helminthiasis continues to pose a significant worldwide health concern due to the rising resistance to traditional anthelmintic medications and the scarcity of viable treatments. This study sought to provide a scientific foundation for the anthelmintic efficacy of Nymphoides hydrophyllum using integrated GC-MS phytochemical profiling, network pharmacology, and molecular docking. GC-MS analysis identified numerous phytoconstituents, with phytol, squalene, and stigmasterol selected for additional computational analysis due to their pharmacological significance and drug-likeness. Network pharmacology research revealed several therapeutic targets linked to kinase-mediated signalling, oxidative stress management, immunological modulation, and cellular survival pathways. GO enrichment analysis revealed substantial participation in protein phosphorylation, membrane-associated signalling, and kinase activity. KEGG pathway enrichment demonstrated a substantial correlation with ErbB signalling, EGFR tyrosine kinase inhibitors resistance, the PD-L1/PD-1 checkpoint pathway, Th17 cell differentiation, PI3K-Akt signalling, and HIF-1 signalling pathways. Numerous hub genes, including EGFR, AKT1, MAPK1, MAPK8, JAK1, JAK2, MTOR, PIK3CA, SRC, and PRKCA, were recognised as pivotal regulators within the pathway-target network. Molecular docking studies revealed advantageous binding relationships between the chosen phytocompounds and target proteins, such as EGFR (5F19), AKT1 (2ITY), MAPK1 (2Y9Q), JAK kinase (5IKR), and acetylcholinesterase (4EJN). Among the evaluated compounds, stigmasterol demonstrated the highest binding affinity for EGFR and acetylcholinesterase, while phytol showed a favourable interaction with JAK kinase and Squalene demonstrated moderate binding affinity with acetylcholinesterase. The findings indicate that N. hydrophyllum exhibits significant anthelmintic potential by modulating many signalling pathways and parasite-related cellular mechanisms.
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia due to insulin resistance or deficiency. The imidazole scaffold, a privileged heterocycle in medicinal chemistry, has shown significant promise in targeting key enzymes involved in type 2 DM (T2DM). In this study, eight novel imidazole derivatives were designed, synthesized, and structurally characterized using H-1 NMR, C-13 NMR, and mass spectrometry. Molecular docking studies against alpha-amylase and alpha-glucosidase revealed favourable binding affinities (-7.2 to-8.8 kcal/mol) and strong interactions with key catalytic residues. ADMET predictions using ADMET Lab 3.0 and SwissADME indicated good drug-likeness for most derivatives, and the top docking hit was subjected to a 100 ns molecular dynamics simulation (Desmond), which confirmed complex stability with minimal RMSD fluctuations (similar to 1.8 & Aring;) and persistent hydrogen bonding. In vitro alpha-amylase inhibition assays demonstrated potent activity, with compound SM-04 exhibiting an IC50 of 21.5 +/- 1.2 pM, comparable to the reference drug acarbose (18.9 +/- 1.4 pM). MTT assays on 3T3-L1 cells indicated low cytotoxicity for all compounds. Overall, the synthesized imidazole derivatives displayed promising in silico and in vitro antidiabetic potential, supporting their development as leads for T2DM therapy.
Plant-derived bioactive compounds exploration presents a good approach to discovering new anti-inflammatory agents. Phytoconstituents of Paris polyphylla were explored as an inhibitor of tissue plasminogen activator (tPA) in the present study using an integrated in silico strategy. Molecular docking demonstrated that some of the compounds were highly docked to the tPA active site, with Disogluside docking the best (-10.1 kcal/mol) in comparison to the co-crystal ligand (-10.1 kcal/mol) and the reference drug Nimesulide (-7.2 kcal/mol). Interaction analysis revealed that Disogluside was able to establish stable hydrogen bonds with key catalytic residues such as Thr175, Ser195, Gly216 and Gly219, and established strong hydrophobic interactions. The stability of the Disogluside-tPA complex was confirmed by molecular dynamics simulations (200 ns) with stable RMSD and minimal structural fluctuations. In addition, MM-GBSA computations revealed a favorable binding free energy (Delta Gbind = -65.04 +/- 4.82 kcal/mol), which was primarily driven by van der Waals and lipophilic interactions. The results indicate that Disogluside can be a potential tPA inhibitor with anti-inflammatory implications and should be investigated by additional experiments.
Nilotinib is one of the important second-generation tyrosine kinase inhibitors used in the treatment of chronic myeloid leukemia. The synthesis of Nilotinib involves expensive intermediates like carboxylic acids. Traditional methods of such intermediates involve chemical hydrolysis using acids or bases, leading to the formation of toxic compounds and high consumption of energy. This study focused on the development of a green and economical chemo-enzymatic approach to nilotinib synthesis by making use of a nitrilase biocatalyst. In this study, thirteen nitrilases were screened for their ability to produce carboxylic acid from nitrile, an intermediate of nil otinib under mildly buffered aqueous medium, and NIT-EW 101 was found to be the best enzyme. Time course study of this enzyme showed that 99.37% of the reaction was complete after 48 h. The isolated acid intermediate was then used to synthesize nilotinib by using the Curtius rearrangement and amide coupling. This route offers a sustainable and industry-feasible alternative to the conventional synthesis of Nilotinib.
