Potential targets for the new anti-tuberculosis drug of the diarylquinoline group thiozonide

Introduction. Diarylquinolines are considered a group of optimal candidates for anti-tuberculosis drugs (ATDs) in the treatment of tuberculosis caused by Mycobacterium tuberculosis exhibiting multidrug resistance. Aim. To perform a computer-aided analysis and evaluation of the potential molecular targets of the domestic anti-tuberculosis drug thiozonide using modern bioinformatics approaches. Material and methods. The SEA Search Service was employed to predict the drug targets. Based on the degree of chemical similarity calculated by the Tanimoto coefficient, this service predicts the effect of the investigated ligand on known targets. Compounds from the ChEMBL database were selected for the analysis, and structurally similar molecules were identified using the Tanimoto similarity measure. Possible targets of thiozonide were predicted using the PPB (Polypharmacology Browser for Target Prediction) service, which utilized six different fingerprints and four of their combinations. A significant potential of thiozonide to bind mycobacterial proteins, including those of M. tuberculosis , was revealed. Additionally, computer-based prediction of potential biological targets for thiozonide was carried out using the PPB (Polypharmacology Browser for Target Prediction in ChEMBL) service to analyze its polypharmacology. A search query initiated based on the chemical structure of thiozonide in SMILES format enabled the identification, among various targets listed in the ChEMBL database, of those most likely to interact with the studied compound. Results and discussion. According to the computer screening results, thiozonide demonstrated the most pronounced predicted activity against various representatives of the genus Mycobacterium, including M. tuberculosis . Based on the study findings, the most likely binding targets were the subunits of bacterial ATP synthase. This enzyme plays a central role in cellular energy metabolism by linking ATP synthesis and hydrolysis with proton translocation across the membrane. Although some human proteins were also identified as potential targets for thiozonide, the affinity of thiozonide to these human targets is considered rather low. Conclusion. The study results demonstrate the selective activity of thiozonide against mycobacteria, particularly M. tuberculosis strains. Thiozonide selectively interacts with the key subunits of the bacterial ATP synthase complex, thereby disrupting its catalytic function. Moreover, thiozonide exhibits low affinity towards human targets (affinity not exceeding 0.1).