Abstract
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.
Highlights
Life-threatening infections caused by fungi have increased rapidly, especially for patients that have immunocompromised diseases, such as AIDS, cancer, and organ-transplantation (Bongomin et al, 2017; Lee et al, 2020)
The ligands Flu, Vor, and Itc were successively docked into the receptor, and the optimal binding pose was selected for the further Molecular dynamics (MD) analyses according to the above criteria
We found that Y118 and L376 had significant contributions in inhibitors binding of all four inhibitors systems, Y64, L87, L88, P230, F233, F380, and M508 made outstanding contributions during the longtailed agents (LT) inhibitors binding
Summary
Life-threatening infections caused by fungi have increased rapidly, especially for patients that have immunocompromised diseases, such as AIDS, cancer, and organ-transplantation (Bongomin et al, 2017; Lee et al, 2020). It is reported that fungal diseases kill 1.5 million people per year, whose number is almost equal to the death of tuberculosis, and nearly three times as that of malaria (Brown et al, 2012; Bongomin et al, 2017). To deal with the serious effects of life-threatening fungal infections, the development of antifungal agents has become a widespread concern (Lepesheva et al, 2018). Influencing the growth and replication of fungi by inhibiting CYP51 has become a strategy for the development of antifungal agents (Lepesheva et al, 2008; Choi and Roush, 2017)
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