Recherche in silico de nouveaux composés bioactifs et applications à l’inhibition de la méthionine aminopeptidase.

Abstract

The great emergence of multi-resistant pathogenic microorganisms, due to the misuse and inappropriate use of antibiotics, poses a particularly serious public health problem. Indeed, the resistance of bacteria to antibiotics sometimes makes the therapeutic treatment ineffective, and puts the practitioner in difficult situations, especially when the life of the patient is involved. The solution of this problem is therefore urgent and requires the search for new antimicrobial agents. As such, methionine aminopeptidase (MetAP) is used as an attractive target for developing new antibiotics because it is essential for bacterial survival. MetAP is a metalloprotease that cleaves N-terminal methionine during protein synthesis, a critical step in protein maturation. This work focuses on the in silico virtual screening of the commercial ZINC database to discover inhibitors with higher inhibitory activity against bacterial MetAP. Two filtering operations from the ZINC database have made it possible to retain 200 000 compounds, allowed the 3.700.000 structures proposed, for a virtual screening by FlexX. After this screening, nine chemical compounds of the top hits predicted were purchased and evaluated in vitro. The antimicrobial activity of each MetAP inhibitor was tested by the disc-diffusion assay against two Gram-positive bacteria (Staphylococcus aureus and Mycobacterium smegmatis) and two Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Among the studied compounds, inhibitors ZINC04785369 and ZINC03307916 showed promising antibacterial activity. To further characterize their efficacy, the minimum inhibitory concentration was determined for each compound by the microdilution method which showed significant results. These results suggest that ZINC04785369 and ZINC03307916 are promising molecules for the development of new inhibitors of bacterial MetAP.