Martins Michelle C M R, Pantaleao Simone Q, de Oliveira Almeida Michell, Weber Karen C, Honorio Kathia M
Center for Natural and Human Sciences, Federal University of ABC, 09210-170, Santo Andre, SP, Brazil.
Sao Carlos Institute of Chemistry, University of Sao Paulo, 13566-590, Sao Paulo, SP, Brazil.
Med Chem. 2021;17(3):247-263. doi: 10.2174/1573406416666200129151256.
The enzyme called dipeptidyl peptidase IV (DPP-IV) is related to the glycemic control associated with the stimulation of the pancreas to produce insulin. So, its inhibition is a good strategy for the treatment of type 2 diabetes mellitus.
In this study, we have employed molecular modeling strategies such as CoMFA, molecular docking, molecular dynamics, and binding free energy calculations of a set of DPP-IV inhibitors in order to understand the main characteristics related to the biological activity of these ligands against the enzyme.
The models obtained from CoMFA presented significant values of internal (0.768) and external (0.988) validations. Important interactions with some residues, such as Glu205, Tyr666, Arg125, Ser630, Phe357 and Tyr662, were also identified. In addition, calculations of the electronic properties allowed relating the LUMO and HOMO energies with the biological activity of the compounds studied. The results obtained from the molecular dynamics simulations and the SIE calculations (ΔG) indicated that the inhibitor 40 increases the stability of the DPP-IV target.
Therefore, from this study, it is possible to propose molecular modifications of these DPP-IV inhibitors in order to improve their potential to treat type 2 diabetes.
名为二肽基肽酶IV（DPP-IV）的酶与胰腺受刺激产生胰岛素相关的血糖控制有关。因此，抑制该酶是治疗2型糖尿病的一种有效策略。
在本研究中，我们采用了分子建模策略，如比较分子场分析法（CoMFA）、分子对接、分子动力学以及一组DPP-IV抑制剂的结合自由能计算，以了解这些配体针对该酶的生物活性的主要特征。
从CoMFA获得的模型呈现出显著的内部（0.768）和外部（0.988）验证值。还确定了与一些残基的重要相互作用，如Glu205、Tyr666、Arg125、Ser630、Phe357和Tyr662。此外，电子性质的计算使我们能够将最低未占分子轨道（LUMO）和最高已占分子轨道（HOMO）能量与所研究化合物的生物活性联系起来。分子动力学模拟和表面相互作用能（SIE）计算（ΔG）的结果表明，抑制剂40增加了DPP-IV靶点的稳定性。
因此，通过本研究，可以对这些DPP-IV抑制剂进行分子修饰，以提高其治疗2型糖尿病的潜力。
