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Halilibrahim Ciftci and Belgin Sever and Esra Ayan and Mustafa Can and Hasan DeMirci and Masami Otsuka and Amaç Fatih TuYuN and Hiroshi Tateishi and Mikako Fujita

Ciftci, H., Sever, B., Ayan, E., Can, M., DeMirci, H., Otsuka, M., TuYuN, A. F., Tateishi, H., & Fujita, M. (2022). Identification of New L-Heptanoylphosphatidyl Inositol Pentakisphosphate Derivatives Targeting the Interaction with HIV-1 Gag by Molecular Modelling Studies. Pharmaceuticals, 15(10), 1255. https://doi.org/10.3390/ph15101255

The HIV-1 Gag protein binds to the host cell membrane and assembles into immature particles. Then, in the course of immature virion budding, activated protease cleaves Gag into its main components: MA, CA, NC, and p6 proteins. The highly basic residues of MA predominantly interact with the acidic head of phosphatidyl-inositol-4,5-bisphosphate (PI(4,5)P2) inserted into the membrane. Our research group developed L-Heptanoylphosphatidyl Inositol Pentakisphosphate (L-HIPPO) and previously confirmed that this compound bound to the MA more strongly than PI(4,5)P2 and inositol hexakisphosphate (IP6) did. Therefore, herein we rationally designed eight new L-HIPPO derivatives based on the fact that the most changeable parts of L-HIPPO were two acyl chains. After that, we employed molecular docking for eight compounds via Maestro software using high-resolution crystal structures of MA in complex with IP6 (PDB IDs: 7E1I, 7E1J, and 7E1K), which were recently elucidated by our research group. The most promising docking scores were obtained with benzene-inserted compounds. Thus, we generated a library containing 213 new aromatic group-inserted L-HIPPO derivatives and performed the same molecular docking procedure. According to the results, we determined the nine new L-HIPPO derivatives most effectively binding to the MA with the most favorable scoring functions and pharmacokinetic properties for further exploration.

http://dx.doi.org/10.3390/ph15101255