ABSTRACT An integrated computational workflow was applied to identify potential inhibitors of dengue virus RNA-dependent RNA polymerase (RdRp) after screening of approximately 9,900 bioactive compounds through structure-based virtual screening and molecular docking. Promising hits were further evaluated using density functional theory (DFT), molecular dynamics (MD) simulations, MM/GBSA free energy calculations, principal component analysis (PCA), free energy landscape (FEL) analysis, machine learning – based QSAR, and ADMET profiling. Redocking highlighted F2924-0102, F3299-0084, and F1411-0380 as top candidates, with docking scores of −12.6, −9.7, and −9.1 kcal/mol, respectively, comparable to the reference inhibitor 68 T (−8.6 kcal/mol). Replicated 500 ns MD simulations demonstrated stable conformations with consistent RMSD, RMSF, radius of gyration (RoG), and solvent-accessible surface area (SASA), indicating system stability and convergence. MM/GBSA analysis revealed favourable binding free energies, particularly for F1411-0380 (−64.02 ± 4.94 kcal/mol) and F2924-0102 (−57.73 ± 4.36 kcal/mol), primarily driven by van der Waals and hydrophobic interactions. Energy decomposition confirmed stable binding to catalytic residues. PCA and FEL analyses identified F2924-0102 as the most stable complex. QSAR predicted pIC50 values between 7.110 and 7.279, while ADMET results indicated good pharmacokinetic properties, supporting these compounds as promising RdRp inhibitors.
T. M. Aljarba, Aftab Alam, Gopal Prasad Agrawal et al.· Molecular Simulation· 0 citations
The literature does not have any sustainable high-performance thin-layer chromatographic (HPTLC) methods for concurrently identifying tenofovir (TEN) and emtricitabine (ECT). Therefore, the proposed study develops and verifies a sustainable reverse-phase HPTLC methodology for determining TEN and ECT concurrently in their fixed-dose combination (FDC) products. The wavelength at which TEN and ECT were simultaneously identified was 255 nm. A 70:30 v/v binary mixture of ethanol and water served as the green development system. The method was validated for accuracy, precision, robustness, sensitivity, and specificity according to ICH guidelines. The validated method was applied for the simultaneous determination of TEN and ECT in commercial FDC tablets. The method's greenness, blueness, and whiteness profiles were evaluated using eight different tools: "the analytical eco-scale (AES), chloroform toxicity (ChlorTox), analytical GREEnness (AGREE), modified green analytical procedure index (MoGAPI), complex MoGAPI, blue applicability grade index (BAGI), carbon footprint reduction index (CaFRI), and click analytical chemistry index (CACI)". For both medications, the devised technique was linear in the range of 25-1000 ng/band. In addition, the created approach was proven to be accurate (% recoveries = 99.12-100.70 for TEN and 100.57-101.83 for ECT), precise (% RSD = 0.85-0.99 for TEN and 0.88-0.97 for ECT), sensitive (LOD = 8.50 ng/band for TEN and 8.39 ng/band for ECT, LOQ = 25.51 ng/band for TEN and 25.19 ng/band for ECT), and robust (% RSD = 0.82-0.86 for TEN and 0.94-0.99 for ECT). Using the current method, the amount of TEN in commercial FDC tablet brands A and B was 98.58 ± 1.21% and 101.13 ± 1.30%, respectively. The amount of ECT in FDC brands A and B was 99.82 ± 1.29 and 100.64 ± 1.37%, respectively. The findings of all the greenness, blueness, and whitening tools, such as AES (93), ChlorTox (0.72 g), AGREE (0.77), MoGAPI (85), complex MoGAPI (90), BAGI (85), CaFRI (89), and CACI (87), demonstrated that the current method had the notably sustainable profiles. The greenness parameters of present method were better than reported HPTLC approaches. The findings of the study suggested that the recommended method may be applied to precisely evaluate TEN and ECT in commercial formulations.
P. Alam, Faiyaz Shakeel, Mohammed H. Alqarni et al.· BMC Chemistry· 0 citations