Tripuraneni Naga Srinivas, Azam Mohammed Afzal
Department of Pharmaceutical Chemistry, J.S.S. College of Pharmacy (Constituent College of JSS University, Mysore), Udhagamandalam, 643001, Tamil Nadu, India.
J Mol Model. 2015 Nov;21(11):289. doi: 10.1007/s00894-015-2837-4. Epub 2015 Oct 26.
Phosphodiesterases 4 enzyme is an attractive target for the design of anti-inflammatory and bronchodilator agents. In the present study pharmacophore and atom based 3D-QSAR studies were carried out for pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues. A five point pharmacophore model was developed using 52 molecules having pIC50 values ranging from 9.959 to 3.939. The best predictive pharmacophoric hypothesis AHHRR.3 was characterized by survival score (2.944), cross validated (r(2) = 0.8147), regression coefficient (R(2) = 0.9545) and Fisher ratio (F =173) with 4 component PLS factor. Results explained that one hydrogen bond acceptor, two aromatic rings and two hydrophobic groups are crucial for the PDE4 inhibition. The docking studies of all selected inhibitors in the active site of PDE4 showed crucial hydrogen bond interactions with Asp392, Asn395 Tyr233, and Gln443 residues. The pharmacophoric features R15 and R16 exhibited π-π stacking with His234, Phe414, and Phe446 residues. The generated model was further validated by carrying out the decoy test. The binding free energies of these inhibitors in the catalytic domain of 1XMU were calculated by the molecular mechanics/generalized Born surface area VSGB 2.0 method. The results of molecular dynamics simulation confirmed the extra precision docking-predicted priority for binding sites, the accuracy of docking, and the reliability of active conformations. Pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues in this study showed lower binding affinity toward PDE3A in comparison to PDE4. Outcomes of the present study provide insight in designing novel molecules with better PDE4 inhibitory activity. Graphical Abstract Pyrozolo[1,5-a]pyridines/4,4-dimethylpyrazolones.
磷酸二酯酶4是设计抗炎和支气管扩张剂的一个有吸引力的靶点。在本研究中，对吡唑并[1,5-a]吡啶/4,4-二甲基吡唑啉酮类似物进行了药效团和基于原子的三维定量构效关系研究。使用52个pIC50值范围为9.959至3.939的分子开发了一个五点药效团模型。最佳预测药效团假设AHHRR.3的特征在于生存分数（2.944）、交叉验证（r(2) = 0.8147）、回归系数（R(2) = 0.9545）和费舍尔比率（F =173）以及4个成分的偏最小二乘因子。结果表明，一个氢键受体、两个芳香环和两个疏水基团对PDE4抑制至关重要。所有选定抑制剂在PDE4活性位点的对接研究表明，它们与Asp392、Asn395、Tyr233和Gln443残基存在关键的氢键相互作用。药效团特征R15和R16与His234、Phe414和Phe446残基表现出π-π堆积。通过进行诱饵测试进一步验证了所生成的模型。使用分子力学/广义玻恩表面积VSGB 2.0方法计算了这些抑制剂在1XMU催化结构域中的结合自由能。分子动力学模拟结果证实了高精度对接预测的结合位点优先级、对接的准确性以及活性构象的可靠性。本研究中的吡唑并[1,5-a]吡啶/4,4-二甲基吡唑啉酮类似物与PDE4相比，对PDE3A的结合亲和力较低。本研究结果为设计具有更好PDE4抑制活性的新型分子提供了见解图形摘要吡唑并[1,5-a]吡啶/4,4-二甲基吡唑啉酮。
