Fragment-based virtual screening discovers potential new Plasmodium PI4KIIIβ ligands.

Abstract

Type III beta phosphatidylinositol 4-kinase (PI4KIIIβ) is the only clinically validated drug target in Plasmodium kinases and therefore a critical target in developing novel drugs for malaria. Current PI4KIIIβ inhibitors have solubility and off-target problems. Here we set out to identify new Plasmodium PI4K ligands that could serve as leads for the development of new antimalarial drugs by building a PPI4K homology model since there was no available three-dimensional structure of PfPI4K and virtually screened a small library of ~ 22 000 fragments against it. Sixteen compounds from the fragment-based virtual screening (FBVS) were selected based on ≤ - 9.0 kcal/mol binding free energy cut-off value. These were subjected to similarity and sub-structure searching after they had passed PAINS screening and the obtained derivatives showed improved binding affinity for PfPI4K (- 10.00 to - 13.80 kcal/mol). Moreover, binding hypothesis of the top-scoring compound (31) was confirmed in a 100 ns molecular dynamics simulation and its binding pose retrieved after the system had converged at about 10 ns into the evolution was described to lay foundation for a rationale chemical-modification to optimize binding to PfPI4K. Overall, compound 31 appears to be a viable starting point for the development of PPI4K inhibitors with antimalarial activity.

• Authors: Akachukwu Ibezim, Mbanefo S Madukaife, Sochi C Osigwe, Nadja Engel, Ramanathan Karuppasamy, Fidele Ntie-Kang
• Journal: BMC chemistry (BMC Chem) Vol. 16 Issue 1 Pg. 19 (Mar 24 2022) ISSN: 2661-801X [Electronic] Switzerland
• PMID: 35331319 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).