Docking-based methodology for the understanding of key interactions involving serine-β-lactamase inhibitors

Antimicrobial resistance is a global public health problem. Resistance to antibiotics can be related with the expression of β-lactamases, which inactivate antibiotics containing the β-lactam ring. Potential inhibitors can be selected or designed based on the understanding of ligand-enzyme interactions targeting inhibitory activity. In this sense, we describe herein a docking-based methodology to analyze interactions for 58 ligands presenting activity in serine-β-lactamase (PDB 1ERM). All scoring functions of CSD-GOLD were used to validate the methodology through redocking, with GOLDScore being the best one. Ligands were constructed with BIOVIA-DSV (pH = 7.4), optimized through PM7 semi-empirical method, from MOPAC2016 package, using CSD-Mercury software. Hydrogen interactions between the inhibitors and key-residues were observed: S70, S130, S235, K73, K234, N132 and G166. Additionally, alkyl-alkyl interactions involving V216 and M260, as well as π-alkyl interactions with Y105. Novel designed compounds able to interact with these key residues are promising to present bioactivity against serine-β-lactamases.