Conformational analysis of different tautomers of some antibiotics

Antibiotics are among the most commonly prescribed medications and are among the most widely used drugs, essential for treating various bacterial infections. However, these molecules adopt different tautomeric conformations in the cellular environment. Therefore, understanding tautomerism in antibiotics is crucial for their recognition by receptors and the design of more effective antibiotics. In this study, a systematic conformational analysis of 23 Food and Drug Administration (FDA)-approved antibiotics across five major classes is performed to identify their most stable and active tautomeric conformations in biological media. In doing so, 105 tautomers of different antibiotics were generated. It is found that Doxycycline favours three degenerate tautomeric conformations and therefore, all these conformers can influence the receptor binding. However, other antibiotics exhibited a single distinct energetically favourable tautomeric conformation. The second most stable tautomer of all antibiotics, except Doxycycline, is ~8-27 kcal/mol less stable than its most stable counterpart. Hence, they may rarely populate in cells. However, the docking scores of the two most stable tautomers bound to their protein and DNA receptors are comparable. It is therefore proposed that the two most stable tautomers of each antibiotic should be considered to explore their substrate-inhibitory activities.

Initially, the ωB97X-D dispersion-corrected density functional theoretic method and 6-31 + G* basis set were used to optimize all tautomers of different antibiotics in the implicit aqueous medium. Subsequently, the ωB97X-D/AUG-cc-pVDZ level of theory was used to refine total electronic energies in the aqueous medium. The SCRF and IEFPCM methods were used to model the aqueous medium. The Gaussian 09 program was used for geometry optimizations and binding energy calculations. Autodock 1.5.7 was used for the molecular docking of the two most stable tautomers of different antibiotics into the substrate active site of their receptors.