a Faculty of Pharmaceutical Sciences , UCSI University , No. 1, UCSI Heights, Jalan Menara Gading, Taman Connaught, 56000 Kuala Lumpur , Federal Territory of Kuala Lumpur , Malaysia.
b Department of Chemistry, Faculty of Science , University of Malaya , 50603 Kuala Lumpur , Federal Territory of Kuala Lumpur , Malaysia.
J Biomol Struct Dyn. 2017 Oct;35(13):2910-2924. doi: 10.1080/07391102.2016.1234417. Epub 2016 Sep 27.
Phosphodiesterase 4 (PDE4) has been established as a drug target for inflammatory diseases of respiratory tract like asthma and chronic obstructive pulmonary disease. The selective inhibitors of PDE4B, a subtype of PDE4, are devoid of adverse effects like nausea and vomiting commonly associated with non-selective PDE4B inhibitors. This makes the development of PDE4B subtype selective inhibitors a desirable research goal. Thus, in the present study, molecular docking, molecular dynamic simulations and binding free energy were performed to explore potential selective PDE4B inhibitors based on ginger phenolic compounds. The results of docking studies indicate that some of the ginger phenolic compounds demonstrate higher selective PDE4B inhibition than existing selective PDE4B inhibitors. Additionally, 6-gingerol showed the highest PDE4B inhibitory activity as well as selectivity. The comparison of binding mode of PDE4B/6-gingerol and PDE4D/6-gingerol complexes revealed that 6-gingerol formed additional hydrogen bond and hydrophobic interactions with active site and control region 3 (CR3) residues in PDE4B, which were primarily responsible for its PDE4B selectivity. The results of binding free energy demonstrated that electrostatic energy is the primary factor in elucidating the mechanism of PDE4B inhibition by 6-gingerol. Dynamic cross-correlation studies also supported the results of docking and molecular dynamics simulation. Finally, a small library of molecules were designed based on the identified structural features, majority of designed molecules showed higher PDE4B selectivity than 6-gingerol. These results provide important structural features for designing new selective PDE4B inhibitors as anti-inflammatory drugs and promising candidates for synthesis and pre-clinical pharmacological investigations.
磷酸二酯酶 4（PDE4）已被确立为治疗哮喘和慢性阻塞性肺疾病等呼吸道炎症性疾病的药物靶点。PDE4B 的选择性抑制剂（PDE4 的一种亚型）没有恶心和呕吐等与非选择性 PDE4B 抑制剂相关的不良反应。这使得开发 PDE4B 亚型选择性抑制剂成为一个理想的研究目标。因此，在本研究中，进行了分子对接、分子动力学模拟和结合自由能计算，以探索基于姜酚化合物的潜在选择性 PDE4B 抑制剂。对接研究的结果表明，一些姜酚化合物对 PDE4B 的选择性抑制作用高于现有的选择性 PDE4B 抑制剂。此外，6-姜酚表现出最高的 PDE4B 抑制活性和选择性。PDE4B/6-姜酚和 PDE4D/6-姜酚复合物的结合模式比较表明，6-姜酚与 PDE4B 的活性位点和控制区域 3（CR3）残基形成了额外的氢键和疏水相互作用，这主要是其对 PDE4B 选择性的原因。结合自由能的结果表明，静电能是阐明 6-姜酚抑制 PDE4B 机制的主要因素。动态互相关研究也支持了对接和分子动力学模拟的结果。最后，根据鉴定的结构特征设计了一个小分子文库，大多数设计的分子对 PDE4B 的选择性高于 6-姜酚。这些结果为设计新型选择性 PDE4B 抑制剂作为抗炎药物提供了重要的结构特征，并为合成和临床前药理研究提供了有前途的候选药物。
