Abstract EN:

This PhD project describes the design of inhibitors of two essential malaria enzymes and of novel modulators of specific nicotinic acetylcholine receptors (nAChRs). Plasmodium vivax subtilase SUB1 is required for parasite egress. We focused our efforts on the design of reversible covalent inhibitors of PvSUB1. We performed covalent docking of potential peptide and peptidomimetic candidates and studied peptide cyclization. Several peptides have shown activity in the submicromolar range and could be resolved after co-crystalization. Plasmodium falciparum lactate dehydrogenase is critical for parasite metabolism. We targeted it by design on the basis of inhibitory cofactor analogs. We have built a combinatorial library aiming to bridge the cofactor and the substrate binding site, while avoiding affecting the human isoenzymes. We screened it in silico and selected about fifty molecules that are under synthesis for ex vivo testing. We also targeted α5 subunit containing nAChRs to address addiction. A multidisciplinary approach has been established. It uses an AChBP engineered chimera, which structure was solved in complex with the first known 5 ligands. This structure, and two comparative modeling models were used to perform in silico screening. A cation-π interaction definition was introduced in the FlexX software and side chain flexibility was allowed in the binding site. An interactive pipeline was developed for the analysis of the virtual screening results and hit molecules have been confirmed by STD-NMR experiments. Deep neural networks models were also built to assess on- and off-target bioactivity prediction in a panel of nAChRs and putative off-targets.