| Autor: |
Akachukwu Ibezim, Mbanefo S. Madukaife, Sochi C. Osigwe, Nadja Engel, Ramanathan Karuppasamy, Fidele Ntie-Kang |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
BMC Chemistry, Vol 16, Iss 1, Pp 1-9 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2661-801X |
| DOI: |
10.1186/s13065-022-00812-2 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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