Caballero Julio
Centro de Bioinformática, Departamento de Bioinformática, Simulación y Modelado (CBSM), Facultad de Ingeniería, Universidad de Talca, Talca 3460000, Chile.
Molecules. 2021 Mar 21;26(6):1765. doi: 10.3390/molecules26061765.
Several years ago, the crystallographic structures of the transient receptor potential vanilloid 1 (TRPV1) in the presence of agonists and antagonists were reported, providing structural information about its chemical activation and inactivation. TRPV1's activation increases the transport of calcium and sodium ions, leading to the excitation of sensory neurons and the perception of pain. On the other hand, its antagonistic inactivation has been explored to design analgesic drugs. The interactions between the antagonists 5,5-diarylpentadienamides (DPDAs) and TRPV1 were studied here to explain why they inactivate TRPV1. The present work identified the structural features of TRPV1-DPDA complexes, starting with a consideration of the orientations of the ligands inside the TRPV1 binding site by using molecular docking. After this, a chemometrics analysis was performed (i) to compare the orientations of the antagonists (by using LigRMSD), (ii) to describe the recurrent interactions between the protein residues and ligand groups in the complexes (by using interaction fingerprints), and (iii) to describe the relationship between topological features of the ligands and their differential antagonistic activities (by using a quantitative structure-activity relationship (QSAR) with 2D autocorrelation descriptors). The interactions between the DPDA groups and the residues Y511, S512, T550, R557, and E570 (with a recognized role in the binding of classic ligands), and the occupancy of isoquinoline or 3-hydroxy-3,4-dihydroquinolin-2(1)-one groups of the DPDAs in the vanilloid pocket of TRPV1 were clearly described. Based on the results, the structural features that explain why DPDAs inactivate TRPV1 were clearly exposed. These features can be considered for the design of novel TRPV1 antagonists.
几年前，有报道称瞬时受体电位香草酸亚型1（TRPV1）在激动剂和拮抗剂存在下的晶体结构，提供了有关其化学激活和失活的结构信息。TRPV1的激活会增加钙和钠离子的转运，导致感觉神经元兴奋和疼痛感知。另一方面，人们已经探索了其拮抗失活作用以设计镇痛药物。在此研究了拮抗剂5,5 - 二芳基戊二烯酰胺（DPDA）与TRPV1之间的相互作用，以解释它们为何使TRPV1失活。本研究确定了TRPV1 - DPDA复合物的结构特征，首先通过分子对接考虑配体在TRPV1结合位点内的取向。在此之后，进行了化学计量学分析：（i）比较拮抗剂的取向（使用LigRMSD），（ii）描述复合物中蛋白质残基与配体基团之间的反复相互作用（使用相互作用指纹图谱），以及（iii）描述配体的拓扑特征与其不同拮抗活性之间的关系（使用具有二维自相关描述符的定量构效关系（QSAR））。清楚地描述了DPDA基团与Y511、S512、T550、R557和E570残基（在经典配体结合中具有公认作用）之间的相互作用，以及DPDA的异喹啉或3 - 羟基 - 3,4 - 二氢喹啉 - 2(1) - 酮基团在TRPV1香草酸口袋中的占据情况。基于这些结果，清楚地揭示了解释DPDA使TRPV1失活的结构特征。这些特征可用于设计新型TRPV1拮抗剂。
