Computational and in vitro binding studies of theophylline against phosphodiesterases functioning in sperm in presence and absence of pentoxifylline

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biophysical chemistry Pub Date : 2024-07-14 DOI:10.1016/j.bpc.2024.107294
Gupta Raj , Kulhar Nitin , Suman Abhishek, Sreenath Dey, Eerappa Rajakumara
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Abstract

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.

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茶碱与精子中存在和不存在的磷酸二酯酶的计算和体外结合研究
生育能力是精子各种功能协同作用的结果,这些功能包括获能、运动、趋化、顶体反应,以及最终使卵细胞受精。精子活力不足是导致男性不育的最常见原因。环磷酸腺苷(cAMP)信号是精子活力的基础,而精子中的磷酸二酯酶(PDEs),如 PDE10A、PDE1 和 PDE4,会耗尽环磷酸腺苷(cAMP)信号。因此,PDE 抑制剂(PDEI)类生育药物旨在通过抑制 PDEs 来提高辅助生殖技术(ART)中的精子活力,尽管它们可能会对其他生理变量产生不利影响。例如,在辅助生殖技术中广泛使用的常用药喷托维林(PTX)可提高运动能力,但会导致过早的顶体反应,并对受精卵细胞产生毒性。另一种黄嘌呤衍生药物茶碱(TP)已被重新用于治疗不孕症,但其抑制PDE的机制仍未被探索。在此,我们使用生物物理和计算方法确定了 TP 与 PTX 结合到相同的结合口袋,其亲和力高于 PTX。我们还发现 PTX 和 TP 共同结合到同一个结合袋中,但结合的位点不同。
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来源期刊
Biophysical chemistry
Biophysical chemistry 生物-生化与分子生物学
CiteScore
6.10
自引率
10.50%
发文量
121
审稿时长
20 days
期刊介绍: Biophysical Chemistry publishes original work and reviews in the areas of chemistry and physics directly impacting biological phenomena. Quantitative analysis of the properties of biological macromolecules, biologically active molecules, macromolecular assemblies and cell components in terms of kinetics, thermodynamics, spatio-temporal organization, NMR and X-ray structural biology, as well as single-molecule detection represent a major focus of the journal. Theoretical and computational treatments of biomacromolecular systems, macromolecular interactions, regulatory control and systems biology are also of interest to the journal.
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