Fragment-based virtual screening discovers potential new Plasmodium PI4KIIIβ ligands

Area of Science:

• Medicinal Chemistry
• Parasitology
• Computational Biology

Background:

• Type III beta phosphatidylinositol 4-kinase (PI4KIIIβ) is a validated drug target for malaria.
• Existing PI4KIIIβ inhibitors face challenges with solubility and off-target effects.

Purpose of the Study:

• To identify novel Plasmodium PI4K ligands as potential antimalarial drug leads.
• To address limitations of current PI4KIIIβ inhibitors.

Main Methods:

• Constructed a homology model for Plasmodium falciparum PI4K (PfPI4K) due to the absence of a 3D structure.
• Performed fragment-based virtual screening (FBVS) of approximately 22,000 compounds against the PfPI4K model.
• Selected 16 compounds based on binding free energy (≤ -9.0 kcal/mol), filtered using PAINS, and performed similarity/sub-structure searches.

Main Results:

• Identified 16 promising compounds from FBVS.
• Obtained derivatives with enhanced binding affinity for PfPI4K, ranging from -10.00 to -13.80 kcal/mol.
• Confirmed the binding hypothesis of the top-scoring compound (31) using 100 ns molecular dynamics simulations, with convergence around 10 ns.

Conclusions:

• Compound 31 emerged as a viable starting point for developing new Plasmodium PI4K inhibitors.
• The study lays the foundation for rational chemical modifications to optimize antimalarial drug candidates targeting PfPI4K.