Design and development of dual inhibitors of Plasmodium falciparum PI4K and PKG as lead compound candidates for Malaria

Despite advances in the fight against malaria in recent decades, the emergence of parasite resistance against available antimalarials has been notable, causing extreme concern. Therefore, it is necessary to search for new candidates for antimalarial drugs, preferably with a different mode of action than the available drugs, in order to reduce the chances of resistance. In this sense, the inhibition of parasite protein kinases is an attractive strategy to be explored. These enzymes are extremely important for the parasite’s life cycle, are highly conserved among Plasmodium species and have significant differences when compared to their human homologous enzymes. In this context, dual inhibition of these targets is an excellent strategy to prevent the emergence of resistant strains. Furthermore, guanidine derivatives are promising parasite growth inhibitors. The strategy outlined for the discovery of dual inhibitors will initially consist of better understanding the binding mode of sapanisertib, a known dual inhibitor of these proteins, using molecular docking and molecular dynamics (MD) simulations. Next, relative binding free energy (RBFE) calculations will be made using free energy perturbation (FEP) to quantitatively determine the importance of each substituent group of the reference inhibitor. These studies will indicate the structural determinants responsible for the molecular recognition and affinity of PfPI4K and PfPKG for sapanisertib, and will also allow the construction of multipharmacophoric models. The knowledge generated in the previous step will be used in the search for guanidine derivatives as potential dual inhibitors. To this end, a virtual library of guanidine derivatives will be created and screened, through molecular docking and MD simulations, followed by absolute binding free energy (ABFE) calculations using FEP, considering the two targets under study. The best guanidine derivatives will be selected based on the lowest energy conformations, and will then be optimized with suitable substituent groups and subjected to new simulations to confirm the stability of the new compounds in both enzymes. In this way, the best virtual hits will be idetified for synthesis and experimental determination of the inhibitory activity against the target enzymes and against the parasite. The results obtained in this project will contribute to the development of new inhibitors with an innovative mechanism of action as candidates for lead compounds for malaria. 

Project details

Product Development

Oct 2023 — Sep 2025

Brazil