Journal of Enzyme Inhibition and Medicinal Chemistry (Jan 2021)

Identification of a novel SPT inhibitor WXP-003 by docking-based virtual screening and investigation of its anti-fungi effect

  • Xin Wang,
  • Xin Yang,
  • Xin Sun,
  • Yi Qian,
  • Mengyao Fan,
  • Zhehao Zhang,
  • Kaiyuan Deng,
  • Zaixiang Lou,
  • Zejun Pei,
  • Jingyu Zhu

DOI
https://doi.org/10.1080/14756366.2021.1915301
Journal volume & issue
Vol. 36, no. 1
pp. 1007 – 1015

Abstract

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Serine palmitoyltransferase (SPT) plays the key role on catalysing the formation of 3-ketodihydrosphingosine, which is the first step of the de novo biosynthesis of sphingolipids. SPT is linked to many diseases including fungal infection, making it a potential therapeutic target. Thus, a logical docking-based virtual screening method was used to screen selective SPT inhibitor against fungi, not human. We used myriocin-similarity database to identify compounds with good binding with fungal SPT and poor binding with homology human SPT model. Preliminary bio-assay led to the discovery of a promising inhibitor WXP-003, which displayed good inhibitory activity against diversity fungi strains with MIC ranging from 0.78 to 12.5 μg/mL. WXP-003 could significantly reduce sphingolipids content in fungi and no effect on mouse fibroblast cell line L929. Molecular dynamics simulation depicted that SPT/WXP-003 complex formed the favoured interactions. Taken together, discovery of WXP-003 provided valuable guide for the development of novel anti-fungal agents.

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