Piper-amides exhibit diverse biological activities, including antimelanogenic effects. In our previous studies, we identified a potent piper-amide derivative that inhibited melanogenesis via the TRPM1 calcium channel. Despite its potential as a therapeutic target, the three-dimensional structure of TRPM1 is still not available. Thus, structure-guided compound design and the discovery of novel inhibitors of melanogenesis have been limited. In the present study, a series of computational methods, including homology modelling, docking, molecular dynamics simulation and field-based pharmacophore modelling, were integrated to explore the structural features of natural piper-amide-like compounds related to the TRPM1 target. These studies suggested the binding mode and provided a 3D pharmacophore model of the ligands, which can be helpful in understanding the TRPM1–ligand interactions at the molecular level and in designing potent antagonists of TRPM1.

哌酰胺表现出多种生物活性，包括促炭疽作用。在我们以前的研究中，我们确定了有效的胡椒酰胺衍生物，可通过TRPM1钙通道抑制黑色素生成。尽管它具有作为治疗靶标的潜力，但TRPM1的三维结构仍然不可用。因此，结构导向的化合物设计和新型黑色素生成抑制剂的发现受到限制。在本研究中，整合了一系列计算方法，包括同源性建模，对接，分子动力学模拟和基于现场的药效团建模，以探索与TRPM1靶标相关的天然哌啶类化合物的结构特征。这些研究提出了结合模式，并提供了配体的3D药效团模型，