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Updated: Apr 27, 2026
Production, Crystallization and Structure Determination of C. difficile PPEP-1 via Microseeding and Zinc-SAD
Published on: December 30, 2016
Computational modelling of potential Zn-sensitive non-β-lactam inhibitors of imipenemase-1 (IMP-1)
Yusuf Oloruntoyin Ayipo1,2, Iqrar Ahmad3, Waleed Alananzeh1
1Centre for Drug Research, Universiti Sains Malaysia, USM, Pulau Pinang, Malaysia.
Abstract:
Antibiotic resistance (AR) remains one of the leading global health challenges, mostly implicated in disease-related deaths. The Enterobacteriaceae-producing metallo-β-lactamases (MBLs) are critically involved in AR pathogenesis through Zn-dependent catalytic destruction of β-lactam antibiotics, yet with limited successful clinical inhibitors. The efficacy of relevant broad-spectrum β-lactams including imipenem and meropenem are seriously challenged by their susceptibility to the Zn-dependent carbapenemase hydrolysis, as such, searching for alternatives remains imperative. In this study, computational molecular modelling and virtual screening methods were extensively applied to identify new putative Zn-sensitive broad-spectrum inhibitors of MBLs, specifically imipenemase-1 (IMP-1) from the IBScreen database. Three ligands, STOCK3S-30154, STOCK3S-30418 and STOCK3S-30514 selectively displayed stronger binding interactions with the enzymes compared to reference inhibitors, imipenem and meropenem. For instance, the ligands showed molecular docking scores of -9.450, -8.005 and -10.159 kcal/mol, and MM-GBSA values of -40.404, -31.902 and -33.680 kcal/mol respectively against the IMP-1. Whereas, imipenem and meropenem showed docking scores of -9.038 and -10.875 kcal/mol, and MM-GBSA of -31.184 and -32.330 kcal/mol respectively against the enzyme. The ligands demonstrated good thermodynamic stability and compactness in complexes with IMP-1 throughout the 100 ns molecular dynamics (MD) trajectories. Interestingly, their binding affinities and stabilities were significantly affected in contacts with the remodelled Zn-deficient IMP-1, indicating sensitivity to the carbapenemase active Zn site, however, with non-β-lactam scaffolds, tenable to resist catalytic hydrolysis. They displayed ideal drug-like ADMET properties, thus, representing putative Zn-sensitive non-β-lactam inhibitors of IMP-1 amenable for further experimental studies.
Insights
Researchers identified novel non-β-lactam inhibitors for metallo-β-lactamases (MBLs) to combat antibiotic resistance. These compounds show strong binding to IMP-1 and possess favorable drug-like properties, offering a promising alternative to current treatments.
Area of Science:
- Computational chemistry and drug discovery
- Molecular biology and enzymology
- Antimicrobial resistance research
Background:
- Antibiotic resistance (AR) is a critical global health threat, with metallo-β-lactamases (MBLs) from Enterobacteriaceae posing a significant challenge.
- MBLs inactivate broad-spectrum β-lactam antibiotics like imipenem and meropenem through Zn-dependent hydrolysis, necessitating the development of novel inhibitors.
- Existing inhibitors for MBLs are limited, highlighting the urgent need for alternative therapeutic strategies.
Purpose of the Study:
- To identify novel, broad-spectrum, and Zn-sensitive inhibitors of MBLs, specifically targeting imipenemase-1 (IMP-1).
- To evaluate the binding interactions, stability, and drug-like properties of potential inhibitor candidates using computational methods.
- To discover non-β-lactam scaffolds that resist catalytic hydrolysis by MBLs.
Main Methods:
- Applied computational molecular modeling and virtual screening using the IBScreen database to identify IMP-1 inhibitors.
- Performed molecular docking and MM-GBSA calculations to assess binding affinities of identified ligands against IMP-1.
- Conducted 100 ns molecular dynamics (MD) simulations to evaluate the thermodynamic stability and compactness of ligand-IMP-1 complexes.
Main Results:
- Identified three ligands (STOCK3S-30154, STOCK3S-30418, STOCK3S-30514) with superior binding interactions and docking scores compared to imipenem and meropenem.
- Ligands demonstrated significant thermodynamic stability and compactness in complex with IMP-1 during MD simulations.
- The binding affinity and stability of ligands were sensitive to the Zn-deficient IMP-1, confirming their interaction with the active Zn site and their non-β-lactam nature, which confers resistance to hydrolysis.
Conclusions:
- The identified non-β-lactam compounds (STOCK3S-30154, STOCK3S-30418, STOCK3S-30514) are promising Zn-sensitive inhibitors of IMP-1.
- These compounds exhibit ideal drug-like ADMET properties, making them suitable candidates for further experimental validation.
- The study provides a foundation for developing new therapeutic agents against MBL-mediated antibiotic resistance.
