PDE4B专一性抑制剂选择性的起源

Origin for the PDE4B-specific inhibitor selectivity

采用分子动力学模拟和结合自由能计算研究了PDE4B抑制剂选择性的起源.首先,探索了模拟时间、溶质介电常数、配体的电荷方案和结合自由能的计算方法对结合自由能预测值准确度的影响,确定最佳模拟条件为:模拟时间40~50 ns,溶质介电常数ε=2,采用MM/GBSA方法以及RESP配体电荷计算方案.接着,通过能量分解分析了抑制剂A33与PDE4B/PDE4D的相互作用,发现PDE4B酶上的Ile410、Gln443、Phe446和Phe506对抑制剂的选择性识别贡献较大.最后,通过位点突变方法探索了PDE4B的CR3螺旋上的Leu502残基对A33选择性所起的作用.当前的工作为设计高活性、高选择性的PDE4B抑制剂提供了有价值的结构与活性关系信息.

The origin of the selectivity of PDE4B inhibitors were investigated by using molecular dynamics simulations and binding free energy calculations.Firstly,the impact of simulation time,solute dielectric constants,ligand charge schemes,and binding free energy calculation methods on the accuracy of the predicted binding free energy were investigated.Optimal simulation conditions were identified as follows:a simulation time of 40~50 ns,a solute dielectric constant(ε)of 2,the employment of the MM/GBSA method,and utilization of the RESP ligand charge calculation scheme.Subsequently,the interactions between inhibitor A33 and PDE4B/PDE4D were analyzed through energy decomposition.It was found that Ile410,Gln443,Phe446,and Phe506 on the PDE4B enzyme contributed significantly to the selective recognition of inhibitors.Finally,the effect of Leu502 residue from the PDE4B CR3 helix on A33 selectivity was explored through site mutation method.The present work provided valuable insight on the structure-activity relationship for designing highly active and selective PDE4B inhibitors.