Structure-based virtual screening and molecular dynamics approaches to identify new inhibitors of Staphylococcus aureus sortase A

J Biomol Struct Dyn. 2024 Feb-Mar;42(3):1157-1169. doi: 10.1080/07391102.2023.2201863. Epub 2023 May 15.


Staphylococcus aureus is a prevalent Gram-positive bacteria leading cause of a wide range of human pathologies. Moreover, antibiotic résistance of pathogenesis bacteria is one of the worldwide health problems. In Gram-positive bacteria, the enzyme of SrtA, is responsible for the anchoring of surface-exposed proteins to the cell wall peptidoglycan. Because of its critical role in Gram-positive bacterial pathogenesis, SrtA is an attractive target for anti-virulence during drug development. To date, some SrtA inhibitors have been discovered most of them being derived from flavonoid compounds, like Myricetin. In order to provide potential hit molecules against SrtA for clinical use, we obtained a total of 293 compounds by performing in silico shape-based screening of compound libraries against Myristin as a reference structure. Employing molecular docking and scoring functions, the top 3 compounds Apigenin, Efloxate, and Compound 8261032 were screened by comparing their docking scores with Myricetin. Furthermore, MD simulations and MM-PBSA binding energy calculation studies revealed that only Compound 8261032 strongly binds to the catalytic core of the SrtA enzyme than Myricetin, and stable behavior was consistently observed in the docking complex. Compound 8261032 showed a good number of hydrogen bonds with SrtA and higher MM-PBSA binding energy when compared to all three molecules. Also, it makes strength interactions with Arg139 and His62, which are critical for SrtA biological activity. This study showed that the development of this inhibitor could be a fundamental strategy against resistant bacteria, but further studies in vitro are needed to confirm this claim.Communicated by Ramaswamy H. Sarma.

Keywords: MD simulations; SrtA inhibitors; Staphylococcus aureus; molecular docking; structure-based virtual screening.

MeSH terms

  • Aminoacyltransferases* / chemistry
  • Bacterial Proteins / chemistry
  • Cysteine Endopeptidases*
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Staphylococcus aureus*


  • sortase A
  • Bacterial Proteins
  • Aminoacyltransferases
  • Cysteine Endopeptidases