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Discovery of Novel Inhibitors of Uridine Diphosphate-N-Acetylenolpyruvylglucosamine Reductase (MurB) from Pseudomonas aeruginosa, an Opportunistic Infectious Agent Causing Death in Cystic Fibrosis Patients
- Source :
- Acebrón-Garciá-De-Eulate, M, Mayol-Llinàs, J, Holland, M T O, Kim, S Y, Brown, K P, Marchetti, C, Hess, J, Di Pietro, O, Mendes, V, Abell, C, Floto, R A, Coyne, A G & Blundell, T L 2022, ' Discovery of Novel Inhibitors of Uridine Diphosphate-N-Acetylenolpyruvylglucosamine Reductase (MurB) from Pseudomonas aeruginosa, an Opportunistic Infectious Agent Causing Death in Cystic Fibrosis Patients ', Journal of Medicinal Chemistry, vol. 65, no. 3, pp. 2149-2173 . https://doi.org/10.1021/acs.jmedchem.1c01684
- Publication Year :
- 2022
- Publisher :
- American Chemical Society (ACS), 2022.
-
Abstract
- Pseudomonas aeruginosa is of major concern for cystic fibrosis patients where this infection can be fatal. With the emergence of drug-resistant strains, there is an urgent need to develop novel antibiotics against P. aeruginosa. MurB is a promising target for novel antibiotic development as it is involved in the cell wall biosynthesis. MurB has been shown to be essential in P. aeruginosa, and importantly, no MurB homologue exists in eukaryotic cells. A fragment-based drug discovery approach was used to target Pa MurB. This led to the identification of a number of fragments, which were shown to bind to MurB. One fragment, a phenylpyrazole scaffold, was shown by ITC to bind with an affinity of Kd = 2.88 mM (LE 0.23). Using a structure guided approach, different substitutions were synthesized and the initial fragment was optimized to obtain a small molecule with Kd = 3.57 μM (LE 0.35).
- Subjects :
- Binding Sites
Cystic Fibrosis
Drug Evaluation, Preclinical
Molecular Conformation
Crystallography, X-Ray
Ligands
Anti-Bacterial Agents
Molecular Docking Simulation
Bacterial Proteins
Catalytic Domain
Drug Discovery
Pseudomonas aeruginosa
Molecular Medicine
Humans
Pyrazoles
Pseudomonas Infections
Oxidoreductases
health care economics and organizations
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Acebrón-Garciá-De-Eulate, M, Mayol-Llinàs, J, Holland, M T O, Kim, S Y, Brown, K P, Marchetti, C, Hess, J, Di Pietro, O, Mendes, V, Abell, C, Floto, R A, Coyne, A G & Blundell, T L 2022, ' Discovery of Novel Inhibitors of Uridine Diphosphate-N-Acetylenolpyruvylglucosamine Reductase (MurB) from Pseudomonas aeruginosa, an Opportunistic Infectious Agent Causing Death in Cystic Fibrosis Patients ', Journal of Medicinal Chemistry, vol. 65, no. 3, pp. 2149-2173 . https://doi.org/10.1021/acs.jmedchem.1c01684
- Accession number :
- edsair.doi.dedup.....4f1c81b53bae22cb7b63156e6235ccdc