Huang Xianfeng, Xu Peng, Cao Yijing, Liu Li, Song Guoqiang, Xu Lei
School of Pharmaceutical Engineering and Life Sciences, Changzhou University Changzhou Jiangsu 213164 PR China
Department of Orthopedics, Second Military Medical University Affiliated Changzheng Hospital Shanghai 200003 China.
RSC Adv. 2018 Aug 29;8(53):30481-30490. doi: 10.1039/c8ra06405a. eCollection 2018 Aug 24.
Cyclic nucleotide phosphodiesterase type 5 (PDE5), exclusively specific for the cyclic guanosine monophosphate (cGMP), is an important drug target for the treatment of erectile dysfunction and pulmonary arterial hypertension (PAH). Although many PDE5 inhibitors have been approved, such as sildenafil, vardenafil, tadalafil and so on, extensive studies have reported some side effects, such as vision disturbance and hearing loss as a result of the amino acid sequence and the secondary structural similarity of other PDEs to the catalytic domain of PDE5. In this study, multiple docking strategies, molecular dynamics (MD) simulations, free energy calculations and decomposition were employed to explore the structural determinants of PDE5 with a series of chromeno[2,3-]pyrrol-9(2)-one derivatives. First, reliable docking results were obtained using quantum mechanics/molecular mechanics (QM/MM) docking. Then, MD simulations and MM/GBSA free energy calculations were used to explore the dynamic binding process and characterize the binding modes of the inhibitors with different activities. The predicted binding free energies are in good agreement with the experimental data, and the MM/GBSA free energy decomposition analysis sheds light on the importance of hydrogen bonds with Gln817, π-π stacks against Phe820 and hydrophobic residues for the PDE5 binding of the studied inhibitors. The structural and energetic insights obtained here are useful for understanding the molecular mechanism of ligand binding and designing novel potent and selective PDE5 inhibitors with new scaffolds.
5型环核苷酸磷酸二酯酶（PDE5）对环磷酸鸟苷（cGMP）具有高度特异性，是治疗勃起功能障碍和肺动脉高压（PAH）的重要药物靶点。尽管许多PDE5抑制剂已获批准，如西地那非、伐地那非、他达拉非等，但大量研究报告了一些副作用，如由于其他磷酸二酯酶与PDE5催化结构域的氨基酸序列和二级结构相似而导致的视力障碍和听力损失。在本研究中，采用了多种对接策略、分子动力学（MD）模拟、自由能计算和分解方法，以探索一系列色烯并[2,3-c]吡咯-9(2)-酮衍生物与PDE5结合的结构决定因素。首先，使用量子力学/分子力学（QM/MM）对接获得了可靠的对接结果。然后，利用MD模拟和MM/GBSA自由能计算来探索动态结合过程，并表征不同活性抑制剂的结合模式。预测的结合自由能与实验数据吻合良好，MM/GBSA自由能分解分析揭示了与Gln817形成氢键、与Phe820形成π-π堆积以及疏水残基对于所研究抑制剂与PDE5结合的重要性。此处获得的结构和能量见解有助于理解配体结合分子机制，并设计具有新骨架结构的新型高效选择性PDE5抑制剂。
