Molecular dynamics simulations reveal insight into key structural elements of aaptamines as sortase inhibitors with free energy calculations

Aaptamine (AAP), demethylaaptamine (DAP), isoaaptamine (IAP) and demethyloxyaaptamine (OAP) are known as selective inhibitors of sortase A (SrtA). The energy decomposition analysis indicates that the interactions between the hydroxyl at C-9 of IAP and Glu44 and between the methyl group at the N-1 of IAP and Gly131 are responsible for inhibition and higher potency. The binding energy difference of SrtA-inhibitors contributes to the difference of the IC50 values of inhibitors. These results imply that hydroxyl at C-9 and the methyl group at the N-1 of aaptamine play a key role in the stabilization of the binding of SrtA-inhibitors.