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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
PubMed

Insights

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.
Keywords:
ANY1FosAFosfomycin resistanceMolecular dynamics

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