Molecular docking studies, in-silico ADMET predictions and synthesis of novel PEGA-nucleosides as antimicrobial agents targeting class B1 metallo-β-lactamases.

Class B1 metallo-β-lactamases (MBLs) are metalloenzymes found in drug resistant bacteria. The enzyme requires zinc ions, along with conserved amino acid coordination for nucleophilic attack of the lactam ring to induce hydrolysis and inactivation of β-lactam and some carbapenem antibiotics. To this date there are no clinically relevant class B1 MBL inhibitors, however L-captopril has shown significant results against NDM-1, the most difficult MBL to inhibit. Herein, we report the synthesis and evaluation of novel nucleoside analogues modified with polyethylene glycolamino (PEGA) as potential inhibitors for class B1 MBLs. Molecular dynamics simulations, using internal coordinate mechanics (ICM) algorithm, were performed on subclass B1 enzyme complex models screened with twenty-one possible PEGA-nucleosides. Analogue A, 3'-deoxy-3'-(2-(2-hydroxyethoxy)ethanamino)-β-D-xylofuranosyluracil showed superior binding, with high specificity to the conserved zinc ions in the class B1 MBL active site by utilizing key β-lactam mimic points in the uridine nucleobase. The PEGA moiety showed chelating activity with zinc and disrupted the metal-binding amino acid geometry. In all subclass B1 proteins tested, analogue A had the most effective inhibition when compared to penicillin or L-captopril. Chemical synthesis was performed by condensation of the corresponding keto ribonucleoside with PEGA, followed by enantioselective reduction of the formed imine to produce the amino derivative with desired configuration. Pharmacokinetic and pharmacodynamic screenings revealed that PEGA-pyrimidine nucleosides are not toxic, nor violate Lipinski's rules. These results suggested that analogue A can be proposed as a potential metalloenzyme inhibitor against the widespread antibiotic resistant bacteria and is worth further in vitro and in vivo investigations.