Ibezim, A., Madukaife, M.S., Osigwe, S.C., Engel, N., Karuppasamy, R., & Ntie-Kang, F. (2021). Fragment-Based Virtual Screening to Discover Potential <em>Plasmodium</em> PI4KIIIβ Ligands. Preprints. https://doi.org/10.20944/preprints202111.0108.v1
Chicago/Turabian Style
Ibezim, A., Ramanathan Karuppasamy and Fidele Ntie-Kang. 2021 "Fragment-Based Virtual Screening to Discover Potential <em>Plasmodium</em> PI4KIIIβ Ligands" Preprints. https://doi.org/10.20944/preprints202111.0108.v1
Abstract
Plasmodium species that cause malaria, a disease responsible for about half a million deaths per annum despite concerted efforts to combat it. The causative agent depends on type III beta phosphatidylinositol 4-kinase (PPI4K) during the development of merozoite. PPI4K is the only clinically validated Plasmodium kinase so far and its inhibitors are effective both in vitro and in vivo. In this work, a small library of ~22 000 fragments was virtually screened using PPI4K homology model to discover potential ligands of the enzyme. 16 virtual hits were selected based on ≤ -9.0 kcal/mol binding energy cut off and were subjected to similarity and substructure searching after they had passed PAINS screening. The derivatives obtained showed improved binding energies, which ranged from -10.00 to -13.80 kcal/mol. Moreover, the topmost ranking compound 31, with interesting drug-like quality was stable within the protein’s binding cavity during the 10 ns molecular dynamics simulation period. In addition, analysis of its binding pose revealed some unique binding interactions with PPI4K active site residues as the basis for the observed improved binding affinity. Overall, compound 31 appears to be a viable starting point for the development of PPI4K inhibitors with antimalarial activity.
Keywords
Plasmodium; malaria; type III beta phosphatidylinositol 4-kinase; virtual screening; homology modeling; molecular dynamics
Subject
Chemistry and Materials Science, Medicinal Chemistry
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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