In silico Docking Analysis for Blocking JUNO‐IZUMO1 Interaction Identifies Two Small Molecules that Block in vitro Fertilization

Nataliia Stepanenko, Omri Wolk, Enrica Bianchi, Gavin James Wright, Natali Schachter-Safrai, Kiril Makedonski, Alberto Ouro, Assaf Ben-Meir, Yosef Buganim, Amiram Goldblum*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Combined hormone drugs are the basis for orally administered contraception. However, they are associated with severe side effects that are even more impactful for women in developing countries, where resources are limited. The risk of side effects may be reduced by non-hormonal small molecules which specifically target proteins involved in fertilization. In this study, we present a virtual docking experiment directed to discover molecules that target the crucial fertilization interactions of JUNO (oocyte) and IZUMO1 (sperm). We docked 913,000 molecules to two crystal structures of JUNO and ranked them on the basis of energy-related criteria. Of the 32 tested candidates, two molecules (i.e., Z786028994 and Z1290281203) demonstrated fertilization inhibitory effect in both an in vitro fertilization (IVF) assay in mice and an in vitro penetration of human sperm into hamster oocytes. Despite this clear effect on fertilization, these two molecules did not show JUNO–IZUMO1 interaction blocking activity as assessed by AVidity-based EXtracellular Interaction Screening (AVEXIS). Therefore, further research is required to determine the mechanism of action of these two fertilization inhibitors.

Original languageEnglish
Article number824629
JournalFrontiers in Cell and Developmental Biology
Volume10
DOIs
StatePublished - 5 Apr 2022
Externally publishedYes

Keywords

  • JUNO–IZUMO1 interaction
  • docking
  • human sperm penetration assay
  • in vitro fertilization
  • non-hormonal contraceptives

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