Exploration of binding mechanism of two potential natural alkaloids as AgrA inhibitors of quorum sensing: molecular docking, molecular dynamics simulation, ADMET and DFT analysis

Currently, targeting bacterial QS is one of the best ways to resolve the problem of bacterial resistance. In agr QS system, the LytTR domain of AgrA regulates the expression of various virulence genes. So, agr QS mediated virulence factors secretion and biofilm formation can be prevented by blocking the DNA binding LytTR domain with small molecules. In this study we docked two natural alkaloids (lanoginosine and liriodenine) with previously homology modelled AgrA proteins ( Chlamydia trachomatis , Enterococcus faecalis , Listeria monocytogenes , and Macrococcus canis) as well as with the template protein of Staphylococcus aureus (PDB ID: 4G4K) using AutoDock 4.2. Both the alkaloids showed excellent binding scores (less than − 8.5 kcal/mol) with all the proteins. 50 ns molecular dynamics simulations and MM/PBSA calculation were performed to study stability of the docked complexes. Liriodenine showed promising MM/PBSA binding free energies ranging from − 71.08 to -134.317 kJ/mol with all the model proteins. DFT based electronic properties of both the alkaloids were calculated using M06-2X/ def2-TZVP level of theory. SwissADME website was used to study the ADMET properties. Both the alkaloids possess very good drug likeness properties and hence, can be used as potential inhibitors against agr QS system.