Abstract
In this study, we present a follow-up on a homology model that was developed and characterised previously in our group. A structure-based virtual screening approach to screen various chemical libraries in a quest to find new or novel inhibitors for the Plasmodium falciparum phosphatidylinositol 4-kinase type III beta (PfPI4KIIIβ) enzyme was the main focus. Virtual screening of the various Maybridge, Medicines for Malaria Venture (MMV) and Pubmed libraries, using Schrödinger Suites, revealed several potential hit compounds. Of the 229 944 compounds screened, 175 hits were found after the extra precision (XP) docking cascade. The top three hits, namely 007, 009 and 018, based on the XP docking scores > -8.5 kcal/mol were subjected to molecular dynamics (MD) simulations. Hit compound 018, from the Maybridge_GPCR library, had the best root mean square deviation (RMSD) and molecular mechanics with generalised Born and surface area solvation (MM/GBSA) results compared to the known ligand, MMV048, for this enzyme. Interestingly, 018 interacted with polar serine and hydrophobic leucine, whereas MMV048 primarily interacted with the hydrophobic valine in the active site of PfPI4KIIIβ. Furthermore, 018 exhibited more hydrogen bond interactions than the known ligand. The ligand-torsion plot undertaken on 018 and MMV048 indicated that 018 is more rigid than MMV048 and this implies better binding to the active site. The MM/GBSA studies indicated MMV048 has a lower solvation score of 1.2528, hence its inferior binding interactions compared to 018 (solvation score of 25.1432). Thus, virtual screening of known libraries can potentially provide new hit compounds and is a good starting point for structure-activity relation (SAR) studies while saving time, costs and resources.