Virtual Screening of the Guanylate Monophosphate Kinase (GMPK) Family: Investigating the Rules of Ligand Specificity

Guanylate kinases (GMPK) from Mycobacterium tuberculosis, Mus musculus and Saccharomyces cereviae were submitted to virtual screening in order to determine protein-ligand interactions specific to M. tuberculosis. The opening of the cleft between CORE, LID and GMP domains was found to have a large influence on the established interactions and on the determination of ligands binding specifically to the M. tuberculosis GMPK. An extended definition of the active site pocket, allowing to be more discriminant between Mycobacterium tuberculosis and M. musculus, is given. A virtual screening run with the extended pocket definition, was used to select compounds having high docking scores on M. tuberculosis GMPK and low ones on M. musculus GMPK. The protein residues involved in hydrogen bonds with ligands were the same than in the GMPK-GMP complex, but the chemical functions of the ligand involved in these hydrogen bonds are often different. On the other hand, the hydrophobic interactions are different from the ones observed in the GMPK-GMP structure, and may be a way to increase the specificity between the M. tuberculosis and M. musculus GMPKs.