Inhibitor discovery against beta lactamase CTX-M-9 from E.coli by molecular docking, MM/PBSA and molecular dynamics studies

Nowadays, antibiotic resistance in bacteria is a major challenge for human health. These new emerging resistances cause ineffectiveness of antibiotics and raising the severity of diseases and treatment costs. One of the most abundant antibiotic resistances is beta lactam antibiotic resistance, especially penicillin and cephalosporin resistances. In most cases, a converting enzyme, named beta lactamase is involved. These enzymes hydrolase the beta lactam-containing antibiotics. Based on Ambler classification, and with regard to their amino acid sequence similarities, these enzymes are classified to four groups; A, B, C and D. In the current study, among 13842 structures, we employed the molecular docking method in virtual screening process to select the potent and effective inhibitors against beta lactamase CTX-M-9 from E.coli. The structures with the lowest free binding energy were conducted to molecular dynamics (MD) studies. Our molecular modeling analysis demonstrates that a compound with Drug-Bank ID of DB01753 has ideal characteristics as potent beta lactamase CTX-M-9 inhibitor. After the 50 ns MD studies, DB01753 interacted with beta lactamase residues Ser 237, Asn 104, Glu 166, Ser 274 and Tyr 105 via hydrogen bonding. MM/PBSA analysis showed that the free energy of binding between DB01753 and beta lactamase was -111.5 kJ.mol-1. Also, ADME analysis exhibited that all pharmaco-kinteic parameters were in reasonable range.