Structure-based Pharmacophore Screening Coupled with QSAR Analysis Identified Potent Natural-product-derived IRAK-4 Inhibitors

Mol Inform. 2021 Dec;40(12):e2100025. doi: 10.1002/minf.202100025. Epub 2021 Aug 24.

Abstract

Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4) has crucial functions in inflammation, innate immunity, and malignancy. Structure-based pharmacophore modeling integrated with validated QSAR analysis was implemented to discover structurally novel IRAK-4 inhibitors from natural products database. The QSAR model combined molecular descriptors with structure-based pharmacophore capable of explaining bioactivity variation of structurally diverse IRAK-4 inhibitors. Manually built pharmacophore model, validated with receiver operating characteristic curve, and selected using the statistically optimum QSAR equation, was applied as a 3D-search query to mine AnalytiCon Discovery database of natural products. Experimental in vitro testing of highest-ranked hits identified uvaretin, saucerneol, and salvianolic acid B as active IRAK-4 inhibitors with IC50 values in low micromolar range.

Keywords: IRAK-4; QSAR; cancer; inflammations; natural products; pharmacophore.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Products* / pharmacology
  • Humans
  • Interleukin-1 Receptor-Associated Kinases
  • Models, Molecular
  • Neoplasms*
  • Protein Kinase Inhibitors / chemistry*
  • Quantitative Structure-Activity Relationship

Substances

  • Biological Products
  • Protein Kinase Inhibitors
  • Interleukin-1 Receptor-Associated Kinases