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A molecular model to study FosA enzyme inhibition
Luiz P C Josino1, Cláudio Nahum Alves1, Anderson H Lima1
1Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, 66075-110, Belém, Pará, Brazil.
Journal of Molecular Graphics & Modelling
|July 3, 2021
Summary
A newly discovered small-molecule inhibitor, ANY1, targets the Fosfomycin resistance protein (FosA), a key enzyme in antibiotic resistance. Molecular dynamics simulations reveal favorable electrostatic and van der Waals interactions stabilizing the enzyme-inhibitor complex.
Area of Science:
- Biochemistry
- Structural Biology
- Medicinal Chemistry
Background:
- Fosfomycin resistance protein (FosA) is a metalloenzyme that inactivates the broad-spectrum antibiotic fosfomycin.
- FosA activity contributes to antibiotic resistance, particularly against Gram-positive pathogens.
- Developing inhibitors of FosA is a strategy to restore fosfomycin efficacy.
Purpose of the Study:
- To investigate the molecular interactions between the FosA enzyme and a newly discovered small-molecule inhibitor, ANY1.
- To computationally validate the binding affinity and key interactions of ANY1 with FosA.
- To understand the mechanisms underlying FosA-mediated fosfomycin resistance.
Main Methods:
- Molecular Dynamics (MD) simulations utilizing the AMBER force field.
- Binding free energy calculations to quantify enzyme-inhibitor interactions.
- Analysis of electrostatic, van der Waals, cavitation, reactive field, and non-polar energy components.
Main Results:
- Molecular dynamics simulations successfully reproduced experimental data trends (R² = 77.51%).
- Electrostatic and van der Waals interactions, along with favorable cavitation energies, stabilize the FosA-ANY1 complex.
- Reactive field energies and non-polar interactions were found to be unfavorable for the FosA-ANY1 complex formation.
Conclusions:
- The study provides a detailed molecular understanding of the interactions between FosA and the inhibitor ANY1.
- Computational methods can accurately predict and explain the binding behavior of FosA inhibitors.
- This research supports the development of ANY1 as a potential therapeutic agent to combat fosfomycin resistance.
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