Role of interaction mode of phenanthrene derivatives as selective PDE5 inhibitors using molecular dynamics simulations and quantum chemical calculations.

IF 3.9 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2024-07-30 DOI:10.1007/s11030-024-10944-3

Supawadee Sainimnuan, Aunlika Chimprasit, Supa Hannongbua, Patchreenart Saparpakorn

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引用次数: 0

Abstract

Phosphodiesterase type 5 (PDE5) inhibitors play a crucial role in blocking PDE5 to improve erectile dysfunction (ED). However, most PDE5 drugs revealed side effects including the loss of vision due to the PDE6 inhibition. Phenanthrene derivatives isolated from E. macrobulbon were previously reported as PDE5 inhibitors. Two phenanthrene derivatives (cpds 1-2) revealed better inhibition to PDE5 than PDE6 and cpd 1 is more selective to PDE5 than cpd 2. To elucidate why the phenanthrene derivatives could inhibit PDE5 and PDE6, their binding modes were investigated using molecular dynamics simulations and quantum chemical calculations, as compared to the PDE5 drugs. From the results, all four drugs and phenanthrene derivatives revealed similar π-π interactions to Phe820 in PDE5. Additional H-bond interaction to Gln817 in PDE5 resulted in better PDE5 inhibition of vardenafil and tadalafil. Moreover, cpds 1-2 were able to form the H-bond interaction with Asp764 in PDE5. In the case of the PDE6, the loss of π-π interaction to Phe776 and H-bond interaction to Gln773 indicated the important points for losing the PDE6 inhibition. In conclusion, to develop the new potent PDE5 inhibitors, not only the important interaction with PDE5 but also the interaction with PDE6 should be considered. In phenanthrene derivatives, the middle ring was significant to form π-π interactions to Phe820 in PDE5 and hydroxyl substituent was also the key part to form the H-bond interaction with Asp764 in PDE5. Principal component analysis (PCA) and free energy landscape (FEL) analysis indicated the stability of the system. The bioavailability, drug-likeness, and pharmacokinetics of phenanthrene derivatives were also predicted. These derivatives revealed good drug-likeness and GI absorption. The obtained results showed that phenanthrene derivatives could be interesting for the development of PDE5 inhibitors in the future.

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利用分子动力学模拟和量子化学计算研究菲类衍生物作为选择性 PDE5 抑制剂的相互作用模式的作用。

5 型磷酸二酯酶（PDE5）抑制剂在阻断 PDE5 以改善勃起功能障碍（ED）方面发挥着重要作用。然而，大多数 PDE5 药物都有副作用，包括因抑制 PDE6 而导致视力下降。以前曾有报道称，从大球藻中分离出的菲类衍生物是 PDE5 抑制剂。两种菲类衍生物（cpds 1-2）对 PDE5 的抑制作用优于 PDE6，而且 cpd 1 对 PDE5 的选择性高于 cpd 2。为了阐明菲类衍生物抑制 PDE5 和 PDE6 的原因，我们使用分子动力学模拟和量子化学计算研究了它们与 PDE5 药物的结合模式。结果表明，所有四种药物和菲类衍生物都与 PDE5 中的 Phe820 有类似的 π-π 相互作用。与 PDE5 中 Gln817 的额外 H 键相互作用使伐地那非和他达那非对 PDE5 的抑制作用更强。此外，cpds 1-2 还能与 PDE5 中的 Asp764 形成 H 键相互作用。对于 PDE6，Phe776 失去了 π-π 相互作用，Gln773 失去了 H-bond 相互作用，这表明 PDE6 失去抑制作用的重要原因。总之，要开发新的强效 PDE5 抑制剂，不仅要考虑与 PDE5 的重要相互作用，还要考虑与 PDE6 的相互作用。在菲类衍生物中，中间环是与 PDE5 中的 Phe820 形成 π-π 相互作用的重要环节，羟基取代基也是与 PDE5 中的 Asp764 形成 H 键相互作用的关键部分。主成分分析（PCA）和自由能谱（FEL）分析表明了该体系的稳定性。此外，还对菲类衍生物的生物利用度、药物亲和性和药代动力学进行了预测。这些衍生物显示出良好的药物亲和性和消化道吸收性。研究结果表明，菲类衍生物在未来可能会成为 PDE5 抑制剂的开发对象。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;