CSD in Action: Fighting Antibiotic Resistance at Merck – Fragment-based Drug Design using CSD-CrossMiner
February 21, 2023
Reporting in the Journal of Medicinal Chemistry, a combined team of medicinal, computational, and structural chemists used a combination of virtual screening and structure-based drug design to identify new inhibitors of key enzymes in the fight against antibiotic resistance.
Antibiotic resistance is of increasing concern. With antibiotic over use, NDM-1 (New Delhi metallo-beta-lactamase 1) has emerged. The enzyme, excreted by bacteria to protect themselves, destroys many penicillin antibiotics. The search for new inhibitors of NDM-1 and similar enzymes is critical in our battle against these so called ‘super bugs.’
The team at Merck identified new inhibitors of metallo-beta-lactamases (MBLs) that hydrolyse beta-lactam antibiotics.
In silico virtual screening of known MBL inhibitors identified targets with activity against NDM-1. Further investigations and metal binding design led to the identification of a pan-MBL inhibitor clinical candidate.
In the investigation of the metal binding conformation of the discovered pan-MBL inhibitors in MBL, several different approaches were taken, including a protein database (PDB) search using CSD-CrossMiner.
“Using CSD-CrossMiner we were able to quickly identify all the structures in the PDB that contain interactions between two Zn ions and a SO2NH group. This was important in our literature survey for our MBLI X-ray crystal structure investigations to review the published landscape.”
“CSD-CrossMiner was used to validate the proposed binding conformation of our pan-MBL inhibitor where the N atom of the SO2NH group interacts with one of Zn ions. CSD-CrossMiner is a valuable tool in our drug discovery research.”Dr Li Xiao, Computational and Structural Chemistry, Merck & Co., Inc.
Studies in vivo of the identified candidate showed effectiveness in lowering antibiotic resistance when used in combination with the intravenous β-lactam antibiotic Imipenem.
The battle against antibiotic resistance continues.
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Read the full paper – Rapid Evolution of a Fragment-like Molecule to Pan-Metallo-Beta-Lactamase Inhibitors: Initial Leads toward Clinical Candidates, M. Mandal and Li Xiao et al., J. Med. Chem. 2022, 65, 24, 16234–16251. https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00766.
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