基于结构的虚拟筛选方法鉴定 PDE5 的潜在抑制剂。
Identification of Potential Inhibitors of PDE5 based on Structure-based Virtual Screening Approaches.
机构信息
Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou 213001, China.
Department of Radiology, Weifang Second People's Hospital, Weifang 261041, China.
出版信息
Curr Comput Aided Drug Des. 2023;19(3):234-242. doi: 10.2174/1573409919666221208143327.
BACKGROUND
Phosphodiesterase type 5 (PDE5), exclusively specific for cyclic guanidine monophosphate (cGMP), a potential target for the therapy of various diseases, and PDE5 inhibitors could be used as a treatment for erectile dysfunction (ED) or chronic pulmonary hypertension.
OBJECTIVE
In the present study, we carried out an integrated computer-aided virtual screening technique against the natural products in the ZINC database to discover potential inhibitors of PDE5.
METHODS
Pharmacophore, molecular docking and ADMET (Absorption, distribution, metabolism, excretion and toxicity) properties filtration were used to select the PDE5 inhibitors with the best binding affinities and drug-like properties. The binding modes of PDE5 inhibitors were investigated, and these complexes' stabilities were explored by molecular dynamic simulations and MM/GBSA free energy calculations.
RESULTS
Two natural compounds (Z171 and Z283) were identified and may be used as a critical starting point for the development of novel PDE5 inhibitors. The MM/GBSA free energy decomposition analysis quantitatively analyzed the importance of hydrophobic interaction in PDE5- ligands binding.
CONCLUSION
In this study, we identified two novel natural compounds from the ZINC database to effectively inhibit PDE5 through virtual screening. The novel scaffolds of these compounds can be used as the starting templates in the drug design of PDE5 inhibitors with good pharmacokinetic profiles. These results may promote the de novo design of new compounds against PDE5.
背景
磷酸二酯酶 5（PDE5）是环鸟苷单磷酸（cGMP）的特异性抑制剂，cGMP 是治疗多种疾病的潜在靶点，PDE5 抑制剂可用作治疗勃起功能障碍（ED）或慢性肺动脉高压的药物。
目的
本研究采用整合计算机辅助虚拟筛选技术，从 ZINC 数据库中的天然产物中发现潜在的 PDE5 抑制剂。
方法
利用药效基团、分子对接和 ADMET（吸收、分布、代谢、排泄和毒性）性质过滤来选择具有最佳结合亲和力和类药性的 PDE5 抑制剂。研究了 PDE5 抑制剂的结合模式，并通过分子动力学模拟和 MM/GBSA 自由能计算来探索这些复合物的稳定性。
结果
鉴定出两种天然化合物（Z171 和 Z283），它们可能成为开发新型 PDE5 抑制剂的关键起点。MM/GBSA 自由能分解分析定量分析了疏水相互作用在 PDE5-配体结合中的重要性。
结论
通过虚拟筛选，本研究从 ZINC 数据库中确定了两种新型天然化合物，可有效抑制 PDE5。这些化合物的新型骨架可作为设计具有良好药代动力学特征的 PDE5 抑制剂的药物的起始模板。这些结果可能促进针对 PDE5 的新化合物的从头设计。
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