Background Coxsackie B3 virus (CVB3) poses a significant public health challenge due to the severity of its associated clinical disorders, driving an urgent need for novel therapeutic agents. Building upon previous research that identified potent isoxazole-based antiviral derivatives, two promising candidate compounds (P3 and P4) were previously identified through computational screening. Objective This study aims to propose a viable synthetic pathway for candidate compound P3 via retrosynthetic analysis, validate its binding kinetics through ligand-release channel dynamics, and elucidate the reaction mechanisms governing its synthesis. Methods Retrosynthetic analysis was conducted to establish a synthetic route for compound P3. The potential mechanism of the key 1,3-dipolar cycloaddition reaction was investigated theoretically. To examine the exit pathways and kinetic behavior of the ligands from the receptor active site to the surface, unbinding release simulations were performed using CaverDock software. Results Retrosynthetic design successfully established a plausible synthetic route toward compound P3, with mechanistic predictions confirming that its formation via 1,3-dipolar cycloaddition is thermodynamically controlled. CaverDock channel analysis identified the primary migration tunnels utilized by the ligands, demonstrating that compound P3 exhibits superior unbinding kinetics and release profiles compared to other derivatives. Conclusions These findings corroborate prior QSAR and molecular docking predictions regarding the high efficacy of compound P3. By providing both a synthetic roadmap and vital insights into ligand–receptor interaction dynamics, this work offers a reliable benchmark for the rational design and synthesis of novel CVB3 antiviral therapeutics. However, further experimental validation is required to confirm the in vitro and in vivo efficacy and safety profile of these proposed candidates.
Introduction Excess formation of AGEs (Advanced Glycation End Products) and increased AGE-RAGE (Receptor for Advanced Glycation End Products) interaction with resultant activation of NF-κB (Nuclear Factor Kappa B) signaling are implicated in the pathogenesis of diabetic nephropathy (DN). Interrupting RAGE-mediated NF-κB signaling could be a therapeutic option to treat DN and other AGEs mediated pathologies. Method In this study, the potential of phytochemicals identified from the methanolic leaf extract of Dillenia indica (DI) to interfere with the AGEs-RAGE axis and NF-κB activation using molecular docking, ADME-Tox and molecular dynamic simulation were investigated in silico approaches. Result Using molecular docking screening of 78 DI phytocompounds identified from GC-MS and LC-MS chromatographic techniques, it was found that some compounds such as Somniferine, Catechin, Butin, Cancentrine, Dipiperamide A and O-Methylsomniferine showed indeed better binding with RAGE and NF-κB while Secoisotetrandrine was comparable to the control drugs. ADME-Tox profiling revealed that Secoisotetrandrine had strong affinity to interact with both RAGE and NF-κB with predicted non-nephrotoxicity.Molecular dynamics simulations further revealed structural binding of Secoisotetrandrine with RAGE and NF-κB protein complexes using RMSD, RMSF & RG analysis throughout the trajectory. MMGBSA free binding energy analysis of the bound complexes demonstrated Secoisotetrandrine with superior stability due to stronger dispersion and hydrophobic contributions, although more stable H-bond interactions were observed in positive controlprotein complexes. Discussion AGEs accumulation and their interaction with RAGE contribute to increased intracellular ROS and activate self-perpetuating NF-κB loop. Virtual screening revealed Secoisotetrandrine with stable binding interaction and structural affinity with RAGE and NF-κB, indicating it could interrupt RAGE-mediated NF-κB interaction and might act as a valuable therapeutic way in providing renoprotection from elevated oxidative stress and inflammation in diabetic influenced renal cells. Conclusion The present study evaluates the antioxidant potential of the plant along with the bioactive metabolites from the methanolic extract, which identifies Secoisotetrandrine from the methanolic extract of Dillenia indica leaves by interrupting RAGE/NF-κB signaling. The study predicts Secoisotetrandrine as a potential candidate with favourable drug-likeness and pharmacokinetic properties and as a promising RAGE/NF-κB inhibitor and renoprotective agent. However, further evaluations are needed for its in vitro and in vivo studies as a therapeutic agent against Diabetic Nephropathy.
Background Majoon Sarakhs is a Unani polyherbal pharmacopoeia formulation used as an anthelmintic. Pronounced health-promoting potential was observed when various herbal drugs are combined hence this research aimed to consolidate the implementation of Majoon Sarakhs as a natural antioxidant. Methods Total phenols and flavonoids present in Majoon Sarakhs extract were determined by Folin–Ciocalteu reagent and aluminum chloride, respectively. Markers identification was performed in the extract using HPLC. The antioxidant potential was assessed in vitro by Potassium ferricyanide–trichloroacetic acid–ferric chloride reducing power assay (Oyaizu’s method) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity methods. In silico study was done on secondary metabolites of its natural ingredients versus myeloperoxidase NADPH oxidase. Molecular dynamics, ADME/TOPKAT prediction and drug-likeness were done to further ascertain the in vitro experiments. Results Total phenols and flavonoids were 13.55 µg GAE and 11.472 µg QE equivalents/mL of the tested sample respectively. Majoon Sarakhs displayed antioxidant potential with IC50 of 212 µg/mL in the DPPH assay. Docking studies showed that embelin showed the highest fitting inside the binding centers of NADPH oxidase and myeloperoxidase oxidase, with C-Docker energies of -37.08 and -28.45 kcal/mol, respectively that was further confirmed by molecular dynamics. ADME/TOPKAT prediction reasonable pharmacodynamic, pharmacokinetic, toxicity, and drug properties for some of the tested compounds whereas unfavorable findings were detected for others. Conclusion Incorporation of Majoon Sarakhs, in pharmaceutical products may combat oxidative stress by serving as antioxidant as revealed from preliminary antioxidant activity in cell-free assays whereas additional in vivo, preclinical and safety studies for the whole herbal formulation are recommended.
Introduction Coumarins are privileged scaffolds in medicinal chemistry, exhibiting broad spectra of biological activities; including anticancer, anti-inflammatory, antioxidant, and antimicrobial effects. In the present study, we synthesized a series of coumarin-3-carboxamide derivatives and assessed their potential as anticancer agents. Methods A series of N-R-2-oxo-2H-chromene-3-carboxamide derivatives were synthesized by reacting 2-oxo-2H-chromene-3-carbonyl chloride with the corresponding amines. In silico molecular docking studies were performed against human carbonic anhydrase (hCA) receptors IX and XII. Molecular dynamics simulations were performed for 100 ns to assess the stability of ligand-protein complexes. In vitro cytotoxicity was evaluated using MTT assay against HeLa (cervical cancer) and Vero (normal kidney) cell lines. Anticancer selectivity was determined using the selectivity index (SI). Results Molecular docking studies revealed strong binding affinities of the synthesized derivatives toward both hCA IX and XII. MD simulations showed compound 5 with lowest RMSD fluctuations in complex with hCA IX, and compound 4e with the highest stability toward hCA XII. Among the derivatives, compound 4 h exhibited most promising anticancer activity (IC50 = 43.02 ± 1.36 µM in HeLa; 111.19 ± 1.74 µM in Vero) with a SI of 2.58 indicating selectivity to cancer cells. Standard drug doxorubicin showed superior potency with an SI of 5.78, but few coumarin derivatives demonstrated moderate selectivity. Conclusion Coumarin-3-carboxamide derivatives demonstrated computationally favourable binding affinity toward hCA IX/XII, with compound 4 h exhibiting highest in vitro activity and selectivity. The results can serve as a starting point to propose compound 4 h as a scaffold for further investigation as anticancer agent.
