Fosfomycin resistance protein (FosA) is a metalloenzyme known for catalyzing a nucleophilic addition reaction of glutathione to the epoxide ring of Fosfomycin, a broad-spectrum antibiotic used to combat Gram-positive pathogens. The reaction leads fosfomycin to lose its pharmacological effect, thus promotes antibiotic resistance. A small-molecule FosA inhibitor has been discovered. ANY1 (3-bromo-6-[3-(3-bromo-2-oxo-1H-pyrazolo[1,5-a]pyrimidin-6-yl)-4-nitro-1H-pyrazol-5-yl]-1H-pyrazolo[1,5-a]pyrimidin-2-one) is competitive with the antibiotic for binding the active site of the enzyme. Through Molecular Mechanics methods, using the AMBER force field, we carry out molecular dynamics simulations and binding free energy calculations to investigate the most important interactions between the enzyme and inhibitor. Our results were able to reproduce the trend of experimental data with R² of 77.51%. Furthermore, we have shown that electrostatic and van der Waals interactions, as well as cavitation energies, are favorable for maintaining the enzyme-inhibitor complex, while reactive field energies and non-polar interactions act in an unfavorable way for interactions between FosA and ANY1.

磷霉素抗性蛋白 (FosA) 是一种金属酶，以催化谷胱甘肽与磷霉素环氧化物环的亲核加成反应而闻名，磷霉素是一种用于对抗革兰氏阳性病原体的广谱抗生素。该反应使磷霉素失去药理作用，从而促进抗生素耐药性。已经发现了一种小分子 FosA 抑制剂。ANY1 (3-bromo-6-[3-(3-bromo-2-oxo-1H-pyrazolo[1,5 - a ]pyrimidin-6-yl)-4-nitro-1H-pyrazol-5-yl]- 1H-吡唑并[1,5- a]pyrimidin-2-one) 与抗生素竞争结合酶的活性位点。通过分子力学方法，使用 AMBER 力场，我们进行分子动力学模拟和结合自由能计算，以研究酶和抑制剂之间最重要的相互作用。我们的结果能够以77.51% 的R ²重现实验数据的趋势。此外，我们已经表明静电和范德华相互作用以及空化能有利于维持酶抑制剂复合物，而反应场能和非极​​性相互作用对 FosA 和 ANY1 之间的相互作用不利。