Investigating sulfonamides - Human serum albumin interactions: A comprehensive approach using multi-spectroscopy, DFT calculations, and molecular docking

Abstract

The environmental and health risks associated with sulfonamide antibiotics (SAs) are receiving increasing attention. Through multi-spectroscopy, density functional theory (DFT), and molecular docking, this study investigated the interaction features and mechanisms between six representative SAs and human serum albumin (HSA). Multi-spectroscopy analysis showed that the six SAs had significant binding capabilities with HSA. The order of binding constants at 298 K was as follows: sulfadoxine (SDX): 7.18 × 10⁵ L mol^-1 > sulfamethizole (SMT): 6.28 × 10⁵ L mol^-1 > sulfamerazine (SMR): 2.70 × 10⁴ L mol^-1 > sulfamonomethoxine (SMM): 2.54 × 10⁴ L mol^-1 > sulfamethazine (SMZ): 3.06 × 10⁴ L mol^-1 > sulfadimethoxine (SDM): 2.50 × 10⁴ L mol^-1. During the molecular docking process of the six SAs with HSA, the binding affinity range is from -7.4 kcal mol^-1 to -8.6 kcal mol^-1. Notably, the docking result of HSA-SDX reached the maximum of -8.6 kcal mol^-1, indicating that SDX may possess the highest binding capacity to HSA. HSA-SDX binding, identified as a static quenching and exothermic process, is primarily driven by hydrogen bonds (H bonds) or van der Waals (vdW) interactions. The quenching processes of SMR/SMZ/SMM/SDX/SMT to HSA are a combination of dynamic and static quenching, indicating an endothermic reaction. Hydrophobic interactions are primarily accountable for SMR/SMZ/SMM/SDX/SMT and HSA binding. Competition binding results revealed that the primary HSA-SAs binding sites are in the subdomain IB of the HAS structure, consistent with the results of molecule docking. The correlation analysis based on DFT calculations revealed an inherent relationship between the structural chemical features of SAs and the binding performance of HSA-SAs. The dual descriptor (DD) and the electrophilic Fukui function were found to have a significant relationship (0.71 and -0.71, respectively) with the binding constants of HSA-SAs, predicting the binding performance of SAs and HSA. These insights have substantial scientific value for evaluating the environmental risks of SAs as well as understanding their impact on biological life activities.

Keywords: DFT calculations; Human serum albumin (HSA); Molecular docking; Multi-spectroscopy; Sulfonamides (SAs).