Assis Letícia C, de Castro Alexandre A, Prandi Ingrid G, Mancini Daiana T, de Giacoppo Juliana O S, Savedra Ranylson M L, de Assis Tamiris M, Carregal Juliano B, da Cunha Elaine F F, Ramalho Teodorico Castro
Laboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras (UFLA), 3027, Campus Universitario, Lavras, 37200000, Minas Gerais, Brazil.
Laboratory of Molecular Simulation of Material, Department of Physics, Federal University of Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, MG, CEP 35400-000, Brazil.
J Mol Model. 2018 Oct 2;24(10):303. doi: 10.1007/s00894-018-3837-y.
The serine/threonine protein phosphatase type 5 (PP5) is a promising target for designing new antitumor drugs. This enzyme is a member of the PPP phosphatases gene family, which catalyzes a dephosphorylation reaction: a regulatory process in the signal transduction pathway that controls various biological processes. The aim of this work is to study and compare the inhibition of PP5 by ten cantharidin-like inhibitors in order to bring about contributions relevant to the better comprehension of their inhibitory activity. In this theoretical investigation, we used molecular dynamics techniques to understand the role of key interactions that occur in the protein active site; QM calculations were employed to study the interaction mode of these inhibitors in the enzyme. In addition, atoms in molecules (AIM) calculations were carried out to characterize the chemical bonds among the atoms involved and investigate the orbital interactions with their respective energy values. The obtained results suggest that the Arg275, Asn303, His304, His352, Arg400, His427, Glu428, Val429, Tyr451, and Phe446 residues favorably contribute to the interactions between inhibitors and PP5. However, the Asp271 and Asp244 amino acid residues do not favor such interactions for some inhibitors. Through the QM calculations, we can suggest that the reactional energy of the coordination mechanism of these inhibitors in the PP5 active site is quite important and is responsible for the inhibitory activity. The AIM technique employed in this work was essential to get a better comprehension of the transition states acquired from the mechanism simulation. This work offers insights of how cantharidin-like inhibitors interact with human PP5, potentially allowing the design of more specific and even less cytotoxic drugs for cancer treatments. Graphical Abstract Interactions of cantharidin-like inhibitors with human protein phosphatase-5 in a Mg system.
丝氨酸/苏氨酸蛋白磷酸酶5（PP5）是设计新型抗肿瘤药物的一个有前景的靶点。该酶是PPP磷酸酶基因家族的成员，催化去磷酸化反应：这是信号转导途径中的一个调控过程，控制着各种生物学过程。这项工作的目的是研究和比较十种斑蝥素样抑制剂对PP5的抑制作用，以便为更好地理解它们的抑制活性做出贡献。在这项理论研究中，我们使用分子动力学技术来理解在蛋白质活性位点发生的关键相互作用的作用；采用量子力学计算来研究这些抑制剂在酶中的相互作用模式。此外，还进行了分子中的原子（AIM）计算，以表征所涉及原子之间的化学键，并研究它们各自能量值的轨道相互作用。所得结果表明，Arg275、Asn303、His304、His352、Arg400、His427、Glu428、Val429、Tyr451和Phe446残基有利于抑制剂与PP5之间的相互作用。然而，Asp271和Asp244氨基酸残基对某些抑制剂不利于这种相互作用。通过量子力学计算，我们可以认为这些抑制剂在PP5活性位点的配位机制的反应能量非常重要，并且是抑制活性的原因。这项工作中采用的AIM技术对于更好地理解从机制模拟中获得的过渡态至关重要。这项工作提供了斑蝥素样抑制剂如何与人类PP5相互作用的见解，有可能为癌症治疗设计出更具特异性甚至细胞毒性更小的药物。图形摘要：斑蝥素样抑制剂与镁系统中人类蛋白磷酸酶-5的相互作用。
