Computational Docking of β-Lactamase Inhibitors to the Mycobacterium tuberculosis β-Lactamase BlaC Structure (PDB ID: 7K8F)

Beta-lactam antibiotics are widely used, yet bacterial beta-lactamases can hydrolyze the beta-lactam ring and cause drug resistance. Beta-lactamase inhibitors (BLIs) are co-administered to protect antibiotics by occupying or inactivating the enzyme active site. Here, we used structure-based molecular docking to compare three BLIs (clavulanic acid, vaborbactam, and nacubactam) against BlaC, a class A β-lactamase from Mycobacterium tuberculosis (M. tuberculosis) that contributes to β-lactam antibiotic resistance, using a BlaC structure captured with ceftriaxone (Protein Data Bank ID: 7K8F) [1], in order to computationally screen and prioritize inhibitors most likely to bind the BlaC active site before moving to more time- and resource-intensive laboratory experiments. We validated the docking setup by re-docking ceftriaxone into the active site using GNINA docking software [2] with a 20 Angstrom cubic search box (center: 15, 2, 25). The best-scoring re-docked pose showed a root mean square deviation (RMSD) of 1.05 Angstrom from the crystallographic ligand position, supporting the use of this protocol for comparative screening. Docking scores (kcal/mol) and residue contacts within 4 Angstrom were then analyzed for each inhibitor. Nacubactam produced the most negative average score (-7.52) and engaged multiple active-site residues (ASP-241, THR-239, SER-128, LYS-236, THR-218), outperforming clavulanic acid (average -4.96) and modestly exceeding vaborbactam (average -6.71). These results suggest nacubactam is a promising candidate for strong active-site binding in this BlaC model, although enzyme inhibition assays will be required to confirm potency and mechanism.