生育力是精子各种功能(包括获能)之间协同作用的结果,运动性,趋化性,顶体反应,and,最后,卵母细胞的受精。运动不足是男性不育的最常见原因。环磷酸腺苷(cAMP)信号是运动的基础,并被精子中的磷酸二酯酶(PDEs)耗尽,例如PDE10A,PDE1和PDE4。因此,生育药物的PDE抑制剂(PDEI)类别旨在通过抑制PDE来增强辅助生殖技术(ARTs)的运动性,尽管它们可能对其他生理变量产生不利影响。例如,流行的药物己酮可可碱(PTX),广泛用于ART,改善运动,但引起过早的顶体反应,并对受精的卵母细胞产生毒性。另一种源自黄嘌呤的药物,茶碱(TP),被重新用于治疗不孕症,但其抑制PDE的机制仍未被探索。这里,使用生物物理和计算方法,我们确定TP与PTX结合相同的结合袋,亲和力高于PTX.我们还发现PTX和TP共同结合到相同的结合口袋,但在不同的地点。
Fertility is a result of a synergy among the sperm\'s various functions including capacitation, motility, chemotaxis, acrosome reaction, and, finally, the fertilization of the oocyte. Subpar motility is the most common cause of infertility in males. Cyclic adenosine monophosphate (cAMP) signalling underlies motility and is depleted by the phosphodiesterases (PDEs) in sperm, such as PDE10A, PDE1, and PDE4. Therefore, the PDE inhibitor (PDEI) category of fertility drugs aim to enhance motility in assisted reproduction technologies (ARTs) through inhibition of PDEs, though they might have adverse effects on other physiological variables. For example, the popular drug pentoxifylline (PTX), widely used in ARTs, improves motility but causes premature acrosome reaction and exerts toxicity on the fertilized oocyte. Another xanthine-derived drug, theophylline (TP), has been repurposed for treating infertility, but its mechanism of PDE inhibition remains unexplored. Here, using biophysical and computational approaches, we identified that TP binds to the same binding pocket as PTX with higher affinity than PTX. We also found that PTX and TP co-bind to the same binding pocket, but at different sites.