Structure based discovery of small molecule suppressors targeting bacterial lysozyme inhibitors.
The production of lysozyme inhibitors, competitively binding to the lysozyme active site, is a bacterial strategy to prevent the lytic activity of host lysozymes. Therefore, suppression of the lysozyme-inhibitor interaction is an interesting new approach for drug development since restoration of the bacterial lysozyme sensitivity will support bacterial clearance from the infected sites. Using molecular modelling techniques the interaction of the Salmonella PliC inhibitor with c-type lysozyme was studied and a protein-protein interaction based pharmacophore model was created. This model was used as a query to identify molecules, with potential affinity for the target, and subsequently, these molecules were filtered using molecular docking. The retained molecules were validated as suppressors of lysozyme inhibitory proteins using in vitro experiments revealing four active molecules.
Laboratory for Biomolecular Modelling and BioMacS, Katholieke Universiteit Leuven, Celestijnenlaan 200G bus 2403, 3001 Heverlee, Leuven, Belgium. arnout.voet@fys.kuleuven.be
Arnout
A
Voet
Lien
L
Callewaert
Tim
T
Ulens
Lise
L
Vanderkelen
Joris M
JM
Vanherreweghe
Chris W
CW
Michiels
Marc
M
De Maeyer
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009113:Muramidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D011994:Recombinant Proteins; D009113:Muramidase