PDF(Pubmed)
Abstract：
In recent years, the awareness that pesticides can have other effects apart from generic toxicity is growing. In particular, several pieces of evidence highlight their influence on human fertility. In this study, we investigated, by a virtual screening approach, the binding between pesticides and proteins present in human gametes or associated with reproduction, in order to identify new interactions that could affect human fertility. To this aim, we prepared ligand (pesticides) and receptor (proteins) 3D structure datasets from online structural databases (such as PubChem and RCSB), and performed a virtual screening analysis using Autodock Vina. In the comparison of the predicted interactions, we found that famoxadone was predicted to bind Cellular Retinol Binding Protein-III in the retinol-binding site with a better minimum energy value of -10.4 Kcal/mol and an RMSD of 3.77 with respect to retinol (-7.1 Kcal/mol). In addition to a similar network of interactions, famoxadone binding is more stabilized by additional hydrophobic patches including L20, V29, A33, F57, L117, and L118 amino acid residues and hydrogen bonds with Y19 and K40. These results support a possible competitive effect of famoxadone on retinol binding with impacts on the ability of developing the cardiac tissue, in accordance with the literature data on zebrafish embryos. Moreover, famoxadone binds, with a minimum energy value between -8.3 and -8.0 Kcal/mol, to the IZUMO Sperm-Egg Fusion Protein, interacting with a network of polar and hydrophobic amino acid residues in the cavity between the 4HB and Ig-like domains. This binding is more stabilized by a predicted hydrogen bond with the N185 residue of the protein. A hindrance in this position can probably affect the conformational change for JUNO binding, avoiding the gamete membrane fusion to form the zygote. This work opens new interesting perspectives of study on the effects of pesticides on fertility, extending the knowledge to other typologies of interaction which can affect different steps of the reproductive process.
摘要：
近年来,人们越来越意识到，农药除了具有一般毒性外，还会产生其他影响。特别是,一些证据强调了它们对人类生育能力的影响。在这项研究中,我们调查过,通过虚拟筛选方法，农药与人类配子中存在的或与生殖相关的蛋白质之间的结合，以确定可能影响人类生育能力的新相互作用。为了这个目标,我们从在线结构数据库（如PubChem和RCSB）中制备了配体（农药）和受体（蛋白质）3D结构数据集，并使用AutodockVina进行了虚拟筛查分析。在预测的相互作用的比较中，我们发现,预测法莫沙酮在视黄醇结合位点结合细胞视黄醇结合蛋白-III,相对于视黄醇的最小能量值为-10.4Kcal/mol,RMSD为3.77(-7.1Kcal/mol).除了类似的互动网络，通过包括L20、V29、A33、F57、L117和L118氨基酸残基以及与Y19和K40的氢键的额外疏水斑块,法莫沙酮结合更加稳定。这些结果支持了法莫沙酮对视黄醇结合的可能的竞争性作用，并影响了心脏组织的发育能力，根据斑马鱼胚胎的文献资料。此外，法莫沙酮结合，最小能量值在-8.3和-8.0Kcal/mol之间，IZUMO精子-卵子融合蛋白，与4HB和Ig样结构域之间的空腔中的极性和疏水性氨基酸残基网络相互作用。这种结合通过与蛋白质的N185残基的预测氢键更稳定。这个位置的障碍可能会影响JUNO结合的构象变化，避免配子膜融合形成合子。这项工作为研究农药对生育力的影响开辟了新的有趣视角，将知识扩展到其他类型的相互作用，这些相互作用可能会影响生殖过程的不同步骤。
