{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["16(1)"],"submitter":["Ibezim A"],"pubmed_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."],"journal":["BMC chemistry"],"pagination":["19"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8944149"],"repository":["biostudies-literature"],"pubmed_title":["Fragment-based virtual screening discovers potential new Plasmodium PI4KIIIβ ligands."],"pmcid":["PMC8944149"],"pubmed_authors":["Osigwe SC","Karuppasamy R","Ibezim A","Madukaife MS","Ntie-Kang F","Engel N"],"additional_accession":[]},"is_claimable":false,"name":"Fragment-based virtual screening discovers potential new Plasmodium PI4KIIIβ ligands.","description":"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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Mar","modification":"2025-04-04T22:12:34.839Z","creation":"2025-04-04T22:12:34.839Z"},"accession":"S-EPMC8944149","cross_references":{"pubmed":["35331319"],"doi":["10.1186/s13065-022-00812-2"]}}