原花青素通过抑制PDE5A活性改善大鼠勃起功能。

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-04-30 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S514209

Yudong Su, Jinman Shui, Danshi Qi, Jie Bai, Xiaoxia Xu, Yongchun Huang, Ruilian Li, Qiong Wu, Haiyan Wang, Chengzhu Cao, Zhanhai Su, Shoude Zhang

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引用次数: 0

摘要

目的：勃起功能障碍（ED）是男性性功能障碍的一种常见形式，主要使用磷酸二酯酶5型抑制剂（PDE5Is）治疗。我们之前的研究强调原花青素是一种天然化合物，是一种非常有效的PDE5I。在目前的研究中，我们打算通过体外和体内评估进一步验证原花青素对PDE5A的抑制活性。方法：通过分子对接、分子动力学（MD）模拟和微尺度热电泳（MST）实验，评估原花青素对PDE5A的结合亲和力。观察原花青素对阴茎海绵体平滑肌细胞（n=5）的毒性作用。此外，我们还评估了其对CCSM细胞（n=5）胞内环鸟苷单磷酸（cGMP）水平的影响。通过测定SD大鼠（n=6）灌胃后不同时间血浆中原花青素的吸收情况。随后，在SD大鼠（n=6）中评估原花青素对阴茎海绵体组织海绵体内压（ICP）和cGMP水平的影响。结果：原花青素与PDE5A形成3个氢键，复合物结构稳定，平衡解离常数（KD）为7.77±2.39µmol/L。此外，与对照组相比，原花青素对CCSM细胞表现出最小的细胞毒性，并显著提高细胞内cGMP水平。体内研究表明，原花青素被迅速吸收，在一小时内达到血药浓度峰值。同时，与对照组相比，原花青素显著增加了大鼠的ICP和cGMP水平。结论：原花青素通过靶向PDE5A维持细胞内cGMP水平升高，具有改善ICP的作用。原花青素被认为是治疗ED和其他相关疾病的有前途的PDE5I。

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Procyanidin Improves Erectile Function in Rats by Inhibiting PDE5A Activity.

Purpose: Erectile dysfunction (ED), a prevalent form of male sexual dysfunction, is predominantly treated with Phosphodiesterase type 5 inhibitors (PDE5Is). Our previous research highlighted procyanidin, a natural compound, as a notably effective PDE5I. In the current study, we intend to further validate the inhibitory activity of procyanidin on PDE5A through in vitro and in vivo assessments. This study aims to validate the efficacy of procyanidin as a treatment for ED.

Methods: The binding affinity of procyanidin for PDE5A was assessed by molecular docking, molecular dynamics (MD) simulations, and microscale thermophoresis (MST) assay. The toxicity of procyanidin on penile corpus cavernosum smooth muscle (CCSM) cells (n=5) was evaluated. Additionally, its effects on intracellular cyclic guanosine monophosphate (cGMP) levels in CCSM cells (n=5) were evaluated. The absorption of procyanidin was evaluated by measuring plasma levels at various times after oral gavage to Sprague-Dawley (SD) rats (n=6). Subsequently, the effects of procyanidin on intracavernous pressure (ICP) and cGMP levels in penile cavernous tissue were evaluated in SD rats (n=6).

Results: Procyanidin forms three hydrogen bonds with PDE5A and stabilizes the complex structure, exhibiting equilibrium dissociation constants (K_D) value of 7.77 ± 2.39 µmol/L. Additionally, procyanidin exhibits minimal cytotoxicity toward CCSM cells and significantly elevates intracellular cGMP levels compared to the control group. In vivo studies demonstrate that procyanidin is rapidly absorbed, achieving peak blood concentrations within one hour. Simultaneously, procyanidin significantly increases ICP and cGMP levels in rats compared to the control group.

Conclusion: These findings indicate that procyanidin sustains elevated cGMP levels within cells by targeting PDE5A, thereby exhibiting therapeutic efficacy in improving ICP. Procyanidin emerges as a promising PDE5I for treating ED and potentially other related conditions.

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.