Inhibition profiling of Dihydrofolate Reductase (DHFR) by antibacterial agents: Toxic-informatics approach in congenital malformation

The congenital malformations (CMFs) remain a major global health concern, with particularly high prevalence in India. Dihydrofolate reductase (DHFR) is a key enzyme in folate metabolism, essential for embryonic development. The inhibition of DHFR by certain antibacterial drugs that cross the placenta potentially leads to teratogenic effects. The present computational drug-target (DT) network analysis, molecular docking, and structural dynamics are used to investigate the impact of commonly prescribed antibacterial drugs on DHFR. Further chemical network identified DHFR as a central hub with strong associations to antifolates and specific antibiotics. The selected drugs, such as Ceftriaxone, Gentamicin, Cefazolin, Levofloxacin, and Amoxicillin, showed high binding affinities viz -9.1, -8.8, -8.5, -8.4, and -8.4 (kcal/mol) respectively. Among all potential interactions, the Gentamicin formed 4 hydrogen bonds with key residues (TYR1231, SER59, ASN64, and GLN35), while Ceftriaxone formed 3 with (ILE16, SER59, and THR56), suggesting strong interaction and potential functional disruption. Through molecular dynamics simulation, it was confirmed that the potential docked complexes were more stable, with low RMSF values. However, the toxicity profiling flagged all antibiotics, except Gentamicin, for hepatotoxicity, raising safety concerns during pregnancy. This computational study reveals how prolonged exposure to certain antibiotics, especially Ceftriaxone and Gentamicin, may impair DHFR activity and contribute to developmental anomalies.