Computational Design and In Silico Evaluation of Thienothiazolocarboxamide Derivatives as DNA Gyrase Inhibitors: ۲D-QSAR, Molecular Docking, and ADMET Prediction

The search for effective inhibitors targeting essential enzymes involved in DNA replication remains a key strategy in antitubercular drug development. DNA gyrase plays a fundamental role in DNA replication and transcription in Mycobacterium tuberculosis, making it a validated molecular target. In this study, thienothiazolocarboxamide derivatives were investigated as potential DNA gyrase inhibitors using an integrated computational approach. A dataset of ۲۰ thienothiazolocarboxamide derivatives was evaluated using two-dimensional quantitative structure-activity relationship (۲D-QSAR) modeling, molecular docking, and pharmacokinetic (ADMET) prediction to identify structural determinants of activity and binding behavior. The QSAR model demonstrated satisfactory predictive capability following internal and external validation (R²_train = ۰.۹۸۰۹, R²_test = ۰.۷۶۵۹), leave-one-out cross-validation (Q²_LOO = ۰.۹۵۲۸), and Y-randomization analysis, supporting the robustness and predictive stability of the developed model. Docking analysis identified compound ۱۷ (MolDock score = -۹۹.۲۵) as a favorable scaffold among the ۲۰ screened compounds, exhibiting strong binding interactions within the DNA gyrase active site. Consequently, compound ۱۷ was selected as the template for structure-guided optimization, which led to the design of new analogues, among which compounds ۱۷f and ۱۷d demonstrated the most promising performance. Compound ۱۷f showed the strongest predicted binding affinity (MolDock = -۱۵۴.۶۴) and the highest predicted activity (pIC₅₀ = ۸.۴۲۶), while compound ۱۷d demonstrated favorable docking performance (MolDock = -۱۴۹.۹۵) and a comparatively balanced ADMET profile. Overall, compounds ۱۷f and ۱۷d demonstrate promising inhibitory potential against DNA gyrase, supported by favorable binding characteristics and predicted pharmacokinetic properties, warranting further experimental validation as candidate antitubercular agents.

کلیدواژه ها:

Thienothiazolocarboxamide derivatives ، DNA gyrase ، Isoniazid ، Mycobacterium Tuberculosis ، ۲D QSAR