Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
Chem Biol Drug Des. 2019 Apr;93(4):419-429. doi: 10.1111/cbdd.13426. Epub 2019 Feb 19.
Phosphodiesterase type 5 (PDE-5) is an important enzyme involved in the hydrolysis of cyclic guanosine monophosphate (cGMP) to guanosine monophosphate (GMP). The inhibition of this protein leads to the accumulation of cGMP in cells with various biological and therapeutic effects. Several PDE-5 inhibitors exist, with Tadalafil being one of the most commonly studied and used in clinical therapy. In this study, we applied Molecular Dynamics simulations coupled to the ABF (Adaptive Biasing Force) method to study the effect of the mutation on the Gln817 residue (Q817G). The results of the free energy profiles made clear that the affinity of the inhibitor for PDE-5 is dependent on the amino acid residue Gln817. The hydrogen bond made between the side chain of glutamine and the indole ring of Tadalafil results in the stabilization of the ligand in the catalytic site. Despite the prominent role of this interaction, it is important to highlight the contribution of other residues of the catalytic domain for the stabilization of the compound, due to the set of polar, hydrophobic and electrostatic interactions performed by specific amino acid residues.
磷酸二酯酶 5 型（PDE-5）是一种重要的酶，参与环鸟苷单磷酸（cGMP）水解为鸟苷单磷酸（GMP）。该蛋白的抑制作用导致细胞内 cGMP 的积累，具有多种生物学和治疗作用。目前已经存在几种 PDE-5 抑制剂，其中他达拉非是临床治疗中研究和使用最广泛的抑制剂之一。在这项研究中，我们应用分子动力学模拟结合自适应偏置力（ABF）方法研究了突变对 Gln817 残基（Q817G）的影响。自由能图谱的结果清楚地表明，抑制剂与 PDE-5 的亲和力取决于氨基酸残基 Gln817。谷氨酰胺侧链与他达拉非的吲哚环之间形成氢键，导致配体在催化位点的稳定。尽管这种相互作用很重要，但值得强调的是，由于特定氨基酸残基之间的一系列极性、疏水和静电相互作用，催化域的其他残基对化合物的稳定也有贡献。
