Targeting isoprenoid biosynthesis pathway in Staphylococcus lugdunensis: Comparative docking and simulation studies of conventional and allosteric sites

Abstract

The current study establishes the use of in silico subtractive genomics approach, molecular docking and molecular dynamic (MD) simulation studies for identifying and inhibiting a potential therapeutic target protein involved in vital metabolic pathways and is therefore crucial for the survival of the human pathogen Staphylococcus lugdunensis. Filtering all the druggable target proteins based on cellular localization and functional annotation has led to the selection of farnesyl diphosphate synthase (Fds). Fds is the key enzyme involved in isoprenoid biosynthesis pathway. Homology model of the protein was generated via MODELLER and other web-based servers. Most reliable protein model selected on the basis of comparative analysis was used as an input for molecular docking studies performed using a total library of 374 compounds. Both conventional and allosteric binding sites were probed to assess the inhibitor binding potential. Among the studied compounds, non-bisphosphonate bisamidines, compound 160 (GOLD Score 79.8) and compound 193 (GOLD Score 87.84) were the top scoring compounds against the normal and allosteric binding pockets, respectively. MD simulations were applied further to explore the dynamic behaviour of both complexes in order to get an insight into structural and conformational changes induced upon ligand binding. MD simulation results revealed that the allosteric binding pocket was slightly more compact and stable when compared to the conventional binding pocket. Significant conformational changes including considerable side chain movements were observed in the binding site amino acid residues accompanied by rearrangement of the hydrogen bonding pattern in conventional and allosteric binding pockets.