Quantum Mechanical Approach for the Catalytic Mechanism of Dinuclear Zinc Metallo-β-lactamase by Penicillin and Cephalexin: Kinetic and Thermodynamic Points of View

Metallo-β-lactamases (MβL) catalyzing the hydrolytic cleavage of the four-membered β-lactam ring in broad spectrum of antibiotics and therefore inactivating the drug; However, the mechanism of these enzymes is still not well understood. Electronic structure and electronic energy of metallo-β-lactamase active center, two inhibitors of this enzyme including penicillin and cephalexin, and different complexes between these inhibitors and active center of metallo-β-lactamase have been investigated. For both substrates (S), the nucleophilic attack of the substrate amide group to model’s active site dinuclear zinc (E) formed an ES reactive complex that by passing through the first transition state (TS1), first intermediate (INT1), the second intermediate (INT2) and second transition state (TS2) converted to the product. Also, all the thermodynamic functions, ∆Hº, ∆Sº and ∆Gº, to form two transition states, TS1 and TS2, and for the total reaction for two MβL inhibitors are evaluated at 25 °C and 1 atmosphere pressure. In all calculations, solvent effects have been considered in water using PCM method.