Coupling Yeast Surrogate Genetics with In Silico Modelling and Virtual Ligand Screening for Target-based Drug Discovery: the neglected vivax malaria case

Plasmodium vivax (Pv) is a neglected human malaria parasite. Limited therapeutic options and resistance emergence1 accentuate the need for new Plasmodium target-based DDD. Using a target-based approach coupled with in-silico modeling, candidate drugs are screened to find antiparasitic molecules. Thirteen Pv genes were selected based on orthology, non-paralogy, essentiality for functional complementation and redundancy avoidance, between Pv, P. falciparum, P. berghei and H. sapiens (Hs). Within the 6 Sc strains expressing Pv and Hs genes2, protein-modelling and virtual-ligand screens against 3, allowed selection of prospective compounds3. Four out of 65 tested compounds selectively inhibited the strain expressing a Pv enzyme catalyzing binding of fatty-acid to the N-terminal glycine. Activity against Pf show moderate inhibition, with non-impairing cytotoxicity rates4. Tests against a panel of Pf strains resistant to clinically used drugs will elucidate their potential. Promising compounds with antiparasitic activity in-vitro, in-vivo and ex-vivo will be chemically redesigned for improved selectivity.