Computational Prediction and In Vitro Validation of Potential Molecular Targets Associated with Adverse Reactions of Antimicrobial Drugs in Neonates

Abstract

Neonates are particularly susceptible to a range of adverse reactions when administered antimicrobial drugs, including allergic reactions, gastrointestinal discomfort, and hepatic or renal dysfunction. These adverse reactions can have significant long-term impacts on neonatal health. This study aimed to investigate the common molecular targets associated with these adverse reactions using reverse target identification and molecular dynamics (MD) simulations, and to experimentally assess the inhibitory effects of selected drugs on these targets. We initially identified adverse reactions associated with commonly used antimicrobial drugs such as Ceftazidime, Meropenem, Levofloxacin, Cefdinir, and Avibactam through DrugBank. Potential targets for these drugs were predicted using SwissTargetPrediction software, and common targets were identified using a Venn diagram. Molecular docking and MD simulations were conducted to assess the binding affinity and stability of the drug–target interactions. Finally, the inhibitory potential of selected antimicrobial drugs on the target proteins was evaluated through in vitro bioactivity assays. The study identified AKR1B1 and Neprilysin as common potential off-targets. Bioactivity assays confirmed that the tested antimicrobial drugs exhibited significant inhibitory effects on these two proteins, with inhibitory concentration at 50% (IC₅₀) values generally in the micromolar range. MD simulations indicated that the complexes of these drugs with the target proteins maintained relatively stable root mean square deviation (RMSD) values throughout the simulation period. Analysis of intermolecular forces revealed key attractive charge interactions and hydrogen bonds between the drugs and target proteins. This study systematically analyzed the molecular targets associated with antimicrobial drug adverse reactions in neonates by integrating computational and experimental approaches. The findings suggest that these drugs may cause adverse reactions by affecting the function of specific off-target proteins. This discovery provides valuable molecular insights into the mechanisms of adverse reactions and establishes a scientific basis for the rational design of safer drug analogs and for informing future antimicrobial treatment research for neonates.