Identification of New L-Heptanoylphosphatidyl Inositol Pentakisphosphate Derivatives Targeting the Interaction with HIV-1 Gag by Molecular Modelling Studies

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Ciftci H., SEVER B., Ayan E., Can M., DeMirci H., Otsuka M., ...More

PHARMACEUTICALS, vol.15, no.10, 2022 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 15 Issue: 10
  • Publication Date: 2022
  • Doi Number: 10.3390/ph15101255
  • Journal Name: PHARMACEUTICALS
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, CAB Abstracts, EMBASE, Veterinary Science Database, Directory of Open Access Journals
  • Keywords: HIV, Gag, MA, PI(4,5)P2, IP6, molecular modelling, ELECTROSTATIC INTERACTIONS, IN-VITRO, MEMBRANE, MATRIX, BINDING, PROTEIN, PHOSPHATIDYLINOSITOL-(4,5)-BISPHOSPHATE, CONFORMATION, AFFINITY
  • Anadolu University Affiliated: Yes

Abstract

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.