Centro de Bioinformática, Simulación y Modelado (CBSM), Facultad de Ingeniería, Universidad de Talca, Talca, Chile.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):2169-2178. doi: 10.1080/14756366.2022.2110089.
The design of TRPV1 antagonists and agonists has reached a new era since TRPV1 structures at near-atomic resolution are available. Today, the ligand-binding forms of several classical antagonists and agonists are known; therefore, the specific role of key TRPV1's residues in binding of ligands can be elucidated. It is possible to place the well-defined pharmacophore of TRPV1 ligands, conformed by head, neck, and tail groups, in the right pocket regions of TRPV1. It will allow a more thorough use of molecular modelling methods to conduct more effective rational drug design protocols. In this work, important points about the interactions between TRPV1 and capsaicin-like compounds are spelled out, based on the known pharmacophore of the ligands and the already available TRPV1 structures. These points must be addressed to generate reliable poses of novel candidates and should be considered during the design of novel TRPV1 antagonists and agonists.
自从 TRPV1 结构达到近原子分辨率以来，TRPV1 拮抗剂和激动剂的设计已经进入了一个新时代。如今，几种经典拮抗剂和激动剂的配体结合形式已经为人所知；因此，可以阐明 TRPV1 关键残基在配体结合中的特定作用。可以将 TRPV1 配体的明确药效基团（由头部、颈部和尾部基团组成）放置在 TRPV1 的正确口袋区域中。这将允许更彻底地使用分子建模方法来进行更有效的合理药物设计方案。在这项工作中，基于已知的配体药效基团和现有的 TRPV1 结构，详细阐述了 TRPV1 与辣椒素样化合物之间相互作用的要点。在生成新型候选物的可靠构象时必须解决这些要点，并且在设计新型 TRPV1 拮抗剂和激动剂时应考虑这些要点。
