Stepanenko Nataliia, Wolk Omri, Bianchi Enrica, Wright Gavin James, Schachter-Safrai Natali, Makedonski Kiril, Ouro Alberto, Ben-Meir Assaf, Buganim Yosef, Goldblum Amiram
Department of Developmental Biology and Cancer Research, Faculty of Medicine, The Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem, Israel.
Laboratory of Molecular Modeling and Drug Discovery, Faculty of Medicine, School of Pharmacy, The Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem, Israel.
Front Cell Dev Biol. 2022 Apr 5;10:824629. doi: 10.3389/fcell.2022.824629. eCollection 2022.
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 fertilization (IVF) assay in mice and an 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.
复方激素药物是口服避孕药的基础。然而，它们会带来严重的副作用，这对资源有限的发展中国家女性影响更大。非激素小分子可以通过特异性靶向参与受精过程的蛋白质来降低副作用风险。在本研究中，我们进行了一项虚拟对接实验，旨在发现能够靶向JUNO（卵母细胞）和IZUMO1（精子）关键受精相互作用的分子。我们将913,000个分子与JUNO的两个晶体结构进行对接，并根据能量相关标准对它们进行排名。在32个测试候选物中，有两个分子（即Z786028994和Z1290281203）在小鼠体外受精（IVF）试验以及人类精子穿透仓鼠卵母细胞试验中均表现出受精抑制作用。尽管这两个分子对受精有明显作用，但基于亲和力的细胞外相互作用筛选（AVEXIS）评估显示，它们并未表现出JUNO-IZUMO1相互作用阻断活性。因此，需要进一步研究以确定这两种受精抑制剂的作用机制。
