The sterol 14α demethylase enzyme (CYP51) is an important target of fungal infections. However, the molecular mechanism between triazoles inhibitors and CYP51 remains obscure. In this study, we have investigated the binding mechanism and tunnel characteristic upon four triazoles inhibitors with CYP51 based on the molecular docking and molecular dynamics simulations. The results indicate the four inhibitors stabilize in the binding cavity of CYP51 in a similar binding mode. We discover a hydrophobic cavity (F58, Y64, Y118, L121, Y132, L376, S378, S506, S507, and M508) and the hydrophobic interaction is the main driving force for inhibitors binding to CYP51. The long-tailed inhibitors (posaconazole and itraconazole) have stronger binding affinities than short-tailed inhibitors (fluconazole and voriconazole) because long-tailed inhibitors can form more hydrophobic interactions with CYP51. The tunnel 2f is the predominant pathway for inhibitors ingress/egress protein, which is similar to the other works of CYP51. This study could provide the theoretical basis for the development of efficient azoles inhibitors and may lead a better insight into structure–function relationships of CYP51.

固醇14α脱甲基酶（CYP51）是真菌感染的重要目标。然而，三唑类抑制剂与CYP51之间的分子机制仍然不清楚。在这项研究中，我们基于分子对接和分子动力学模拟研究了四种三唑类抑制剂与CYP51的结合机理和隧穿特性。结果表明四种抑制剂以相似的结合方式稳定在CYP51的结合腔中。我们发现了疏水腔（F58，Y64，Y118，L121，Y132，L376，S378，S506，S507和M508），并且疏水相互作用是抑制剂与CYP51结合的主要驱动力。长尾抑制剂（波沙康唑和伊曲康唑）比短尾抑制剂（氟康唑和伏立康唑）具有更强的结合亲和力，因为长尾抑制剂可与CYP51形成更多的疏水相互作用。隧道2f是抑制剂进入/流出蛋白的主要途径，与CYP51的其他工作相似。这项研究可以为开发高效唑类抑制剂提供理论依据，并且可以更好地了解CYP51的结构与功能之间的关系。