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Title: Fragment-based virtual screening discovers potential new Plasmodium PI4KIIIβ ligands
Author(s): Ibezim, Akachukwu
Madukaife, Mbanefo S.
Osigwe, Sochi C.
Engel, Nadja
Karuppasamy, Ramanathan
Ntie-Kang, Fidele
Issue Date: 2022
Type: Article
Language: English
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.
Open Access: Open access publication
License: (CC BY 4.0) Creative Commons Attribution 4.0(CC BY 4.0) Creative Commons Attribution 4.0
Sponsor/Funder: Publikationsfonds MLU
Journal Title: BMC chemistry
Publisher: Springer International Publishing
Publisher Place: [Cham]
Volume: 16
Original Publication: 10.1186/s13065-022-00812-2
Appears in Collections:Open Access Publikationen der MLU

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