Bustos Daniel, Galarza Christian, Ordoñez Wilson, Brauchi Sebastian, Benso Bruna
Centro de Investigación de Estudios Avanzados del Maule (CIEAM), Vicerrectoría de Investigación y Postgrado, Universidad Católica del Maule, Talca 3460000, Chile.
Laboratorio de Bioinformática y Química Computacional, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Católica del Maule, Talca 3480094, Chile.
ACS Omega. 2023 Mar 24;8(13):11736-11749. doi: 10.1021/acsomega.2c05672. eCollection 2023 Apr 4.
Transient receptor potential (TRP) channels constitute a large group of membrane receptors associated with sensory pathways in vertebrates. One of the most studied is TRPV1, a polymodal receptor tuned for detecting heat and pungent compounds. Specific inhibition of the nociceptive transduction at the peripheral nerve represents a convenient approach to pain relief. While acting as a chemoreceptor, TRPV1 shows high sensitivity and selectivity for capsaicin. In contrast to the drugs available on the market that target the inflammatory system, TRPV1 antagonists act as negative modulators of nociceptive transduction. Therefore, the development of compounds modulating TRPV1 activity has expanded dramatically over time. Experimental data suggest that most agonist and antagonist drugs interact at or near capsaicin's binding site. In particular, the properties of capsaicin's head play an essential role in modulating potency and affinity. Here, we explored a cost-efficient pipeline to predict the effects of introducing chemical modifications into capsaicin's head region. An extensive set of molecules was selected by first considering the geometrical properties of capsaicin's binding site and then molecular docking. Finally, the novel ligands were ranked by combining molecular and pharmacokinetic predictions.
瞬时受体电位（TRP）通道构成了一大类与脊椎动物感觉通路相关的膜受体。研究最多的是TRPV1，它是一种多模式受体，用于检测热和刺激性化合物。在外周神经处特异性抑制伤害性转导是一种方便的缓解疼痛的方法。TRPV1作为一种化学感受器，对辣椒素表现出高敏感性和选择性。与市场上针对炎症系统的药物不同，TRPV1拮抗剂作为伤害性转导的负调节剂。因此，随着时间的推移，调节TRPV1活性的化合物的开发有了显著的扩展。实验数据表明，大多数激动剂和拮抗剂药物在辣椒素结合位点或其附近相互作用。特别是，辣椒素头部的性质在调节效力和亲和力方面起着至关重要的作用。在这里，我们探索了一种经济高效的流程，以预测在辣椒素头部区域引入化学修饰的效果。首先通过考虑辣椒素结合位点的几何性质，然后进行分子对接，选择了大量的分子。最后，通过结合分子和药代动力学预测对新型配体进行排序。
