A molecular modeling approach to discovery of inhibitors of D-alanine:D-alanine ligase
Blaz Vehar Laboratory for Molecular Modeling
National Institute of Chemistry, Slovenia
Abstract:
In recent years it has become apparent that bacterial resistance mechanisms and irrational use of existing drugs generate a constant need for new antimicrobial agents. Modern computational techniques allow us to explore new targets for antimicrobial activity which should lead to a more diverse array of available medicines than those used in therapy of infectious diseases today.
Our group focuses on enzymes from the Mur-ligases pathway responsible for the intracellular steps of peptidoglycan biosynthesis, one of which is the D-alanine:D-alanine ligase. We have employed molecular dynamics simulations and molecular graph-based binding site predictions to study the enzyme properties and behaviour, virtual screening trials and molecular similarity calculations to find its potential inhibitors and several experimental methods to assess their activity. Several lead compounds with promising MIC-values and on-target activity were identified and are being optimized in our ongoing investigation.
