This study examines seventy‐one 1,4‐naphthoquinone scaffold‐bearing compounds with known half‐maximal inhibitory concentration (IC 50 ) against Mycobacterium tuberculosis (Mtb) using QSAR, docking, and molecular dynamics (MD) simulations. The molecular descriptors were computed using PaDEL and ChemDes to create multiple linear regression (MLR) based predictive 2D QSAR models through QSARINS v2.2.4. The statistically suitable five‐descriptor QSAR model demonstrated a correlation coefficient ( R 2 0.7136) and a cross‐validated R 2 ( Q 2 LOO 0.6599). The model exhibited lower values for root mean squared error (RMSE tr 0.2298) and mean absolute error (MAE tr 0.1738), along with a higher concordance correlation coefficient (CCC 0.8329), indicating strong fitness and predictive accuracy. In silico screening of all compounds for physicochemical and medicinal chemistry parameters, followed by docking against five key Tb pathogenesis proteins using Cresset Flare 10.0.1, identified 24 leading candidates. A 200 ns MD simulation revealed good protein‐ligand complex stability of two compounds, 52 and 70 , which was further supported by MM/GBSA calculation. SAR analysis demonstrates that introducing chlorine into the quinone scaffold, in combination with highly lipophilic aryl substituents such as trifluoromethyl, significantly enhances binding affinity. Considering suitable druggability parameters, we suggest compound 70 for further research to confirm its potential as an effective anti‐TB drug.
Computational findings support the prioritization of X14 for further experimental validation in glioblastoma therapy, and generally favorable ADMET profiles were observed, hepatotoxicity alerts were predicted for all compounds, which represents an important limitation supporting the prioritization of X14.
Introduction: The α-amylase enzyme plays a critical role in the digestion of complex carbohydrates. Inhibiting this enzyme offers a promising strategy for improving glucose regulation in diabetic patients. Methods: In this study, a comprehensive computational approach, combining 3D-QSAR modeling, ADMET profiling, molecular docking, molecular dynamics, ligand transport analysis, and retrosynthesis, was used to identify novel ligands with potent inhibitory activity against various indenoquinoxaline-phenylacrylohydrazide hybrids. Results: The optimal 3D-QSAR model, developed using partial least squares (PLS) and Comparative Molecular Similarity Indices Analysis (CoMSIA), demonstrated strong correlation and predictive power (Q2=0.541, R2=0.973, SEE=0.076). ADMET analysis showed that the designed ligands possess acceptable pharmacokinetic and toxicological profiles, supporting their potential for further drug development. Molecular docking revealed that the designed ligands effectively interacted with the active site of α-amylase (PDB ID: 7TAA). Furthermore, molecular dynamics simulations (100 ns) and MM-PBSA free energy calculations confirmed the stability of ligand-enzyme complexes. Ligand transport was further examined using the CaverDock program, tracking the movement of molecules from the enzyme’s active site to its surface. Finally, retrosynthetic analysis was performed to propose feasible synthesis routes for the most active compound. Conclusion: Overall, the findings highlight a promising lead compound for further in vitro and in vivo investigations targeting α-amylase inhibition.
This study highlights natural diterpenoids and coumarin glycosides as promising scaffolds for caspase-1 inhibition and demonstrates that integrating QSAR modeling with structure-based approaches provides an efficient strategy for discovering potential anti-inflammatory drug candidates.
Oxidative stress is a key driver of the pathogenesis of numerous chronic inflammatory and metabolic diseases emphasizing the requirement for the development of potent and selective antioxidant therapeutics. In present study, a series of novel piperazine-linked 1,3,5-triazine derivatives (6a-h) was rationally designed, synthesised and evaluated for antioxidant activity using integrated computational and experimental approaches. Molecular docking studies were carried out against myeloperoxidase (MPO; PDB ID: 1DNU), a heme-containing enzyme involved in reactive oxygen species (ROS) generation, to examine ligand–protein interactions and binding affinities. The synthesized compounds exhibited binding energies ranging from -3.816 to -4.987 kcal/mol. Among them, compound 6f, bearing a para-fluorophenyl substituent, shows the highest binding affinity (-4.987 kcal/mol). The enhanced binding was attributed to the formation of two hydrogen bonds with ARG27 and LEU97 and exceeded the binding energy of the reference antioxidant, ascorbic acid (-4.690 kcal/mol). The antioxidant potential was assessed by the DPPH free radical scavenging assay. Compound 6f displayed the strongest activity with an IC50 value of 14.15 ± 0.14 µM, which was comparable to that of ascorbic acid (IC50 = 14.06 ± 0.18 µM). Structure-activity relationship analysis indicated that the electron-withdrawing substituents at the para-position of aryl ring, together with nitrogen-containing heteroaromatic moieties, improve both binding affinity and free radical scavenging activity. The results identify piperazine-linked 1,3,5-triazine derivatives as promising antioxidant scaffolds and provide a strong basis for future myeloperoxidase inhibition studies and in vivo pharmacological evaluation.
The findings from molecular docking, 500-ns molecular dynamics simulations, MM-GBSA calculations, and alanine scanning analyses collectively corroborate a stable binding mode of BTB11556 within the MPO active site, support further investigation of BTB11556 as a candidate compound associated with MPO-targeted therapeutic strategies.
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