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

doi:10.3389/fcell.2022.824629

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

Front Cell Dev Biol. 2022 Apr 5:10:824629. doi: 10.3389/fcell.2022.824629. eCollection 2022.

Affiliations

¹ Department of Developmental Biology and Cancer Research, Faculty of Medicine, The Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem, Israel.
² Laboratory of Molecular Modeling and Drug Discovery, Faculty of Medicine, School of Pharmacy, The Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem, Israel.
³ Department of Biology, Hull York Medical School, York Biomedical Research Institute, University of York, York, United Kingdom.
⁴ Infertility and IVF Unit, Department of Obstetrics and Gynecology, Hadassah Ein-Kerem Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.

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.

Keywords: JUNO–IZUMO1 interaction; docking; human sperm penetration assay; in vitro fertilization; non-hormonal contraceptives.