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

• Grant number: 23/09209-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): October 01, 2023
• Effective date (End): September 30, 2025
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Rafael Victorio Carvalho Guido
• Grantee: Vinícius Bonatto
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated research grant: 19/17721-9 - The role of Chemistry in holobiont adaptation, AP.TEM

Abstract

Despite significant advancements in the battle against malaria in recent decades, the emergence of drug resistance in the parasite has posed a major challenge and raised considerable concern. Therefore, the search for new antimalarial drug candidates, preferably with distinct modes of action from existing drugs, is crucial to reduce the likelihood of resistance development. In this regard, targeting parasite protein kinases for inhibition represents an attractive strategy worth exploring.In this proposal, we have selected the protein kinases PfPI4K and PfPKG as validated targets for the discovery of new antimalarials. These enzymes play critical roles in the parasite's life cycle, exhibit high degree of structural similarities among Plasmodium species, and possess significant differences compared to their human homologous enzymes. In this sense, dual inhibition of these targets offers an excellent strategy to mitigate the emergence of resistant strains. Furthermore, guanidine derivatives have shown promise as inhibitors of parasite growth.The outlined strategy for discovering dual inhibitors begins with gaining a better understanding of the binding mode of sapanisertib, a known dual inhibitor of PfPI4K and PfPKG, through molecular docking and molecular dynamics (MD) simulations. Subsequently, relative binding free energy (RBFE) calculations using free energy perturbation (FEP) will be conducted to quantitatively assess the significance of each substituent group in the reference inhibitor. These studies will elucidate the structural determinants responsible for the molecular recognition and affinity of sapanisertib for PfPI4K and PfPKG, ultimately aiding in the construction of multipharmacophoric models.The insights obtained from the previous steps will guide the exploration of guanidine derivatives as potential dual inhibitors. A virtual library of guanidine derivatives will be generated and screened using molecular docking and MD simulations, followed by absolute binding free energy (ABFE) calculations using FEP, considering both target enzymes. The top guanidine derivatives will be selected based on their lowest energy conformations, and then optimized with appropriate substituent groups, these new compounds will be subjected to further simulations to confirm the stability in both proteins. This approach will enable the identification of the most promising virtual hits for synthesis and subsequent experimental assessment of their inhibitory activity against the target enzymes and the parasite. The findings of this project will contribute to the development of innovative inhibitors with novel mechanisms of action, serving as leading compounds for malaria treatment. (AU)