Pharmacophore Model for GES-5 Inhibitors

A pharmacophore for GES-5 inhibitors was derived in an analogous way as done previously for KPC-2 [21 (link)]. The structure comparison of GES-5 and KPC-2 was performed using the Molecular Operating Environment (MOE; Chemical Computing Group, Montreal, QC, Canada) and PyMOL (Schrödinger, LLC, New York, NY, USA). The published structures of GES-5 (PDB code 4GNU and 4H8R) and our in-house structure were aligned with the structure of KPC-2 (PDB code 3RXW) to identify key interactions. The final pharmacophore was based on the apo-crystal structure of GES-5, which we have solved for this project (PDB code 6TS9), and the ligand 0JB of CTX-M-9 β-lactamase (PDB code 4DE0). It contained the same features as our previous pharmacophore for KPC-2, namely a hydrogen-bond acceptor feature for interactions with Ser125, Thr230 and Thr232, a hydrophobic π-stacking feature with Trp99 and a hydrogen bond acceptor feature for interaction with Asn127 (Figure 2a). The interactions to Thr230 and Thr232 were set as mandatory for filtering the obtained docking hit list.