Computational assessment of thioether isosteres

J Mol Graph Model. 2018 Mar:80:282-292. doi: 10.1016/j.jmgm.2018.01.018. Epub 2018 Feb 1.


Replacement of the sulfur atom in biologically active diaryl and heteroaryl thioethers (Ar-S-Ar', HAr-S-Ar, and HAr-S-HAr') with any of several one-atom or two-atom linkers can be expected to reduce the susceptibility of the analogue to metabolic oxidation, a well-documented problem for thioethers intended for medicinal chemistry applications. Ab initio calculations indicate how well various proposed thioether isosteric groups, including some new and unusual ones, may perform structurally and electronically in replacing the bridging sulfur atom. Four of these are calculationally evaluated as proposed substructures in Axitinib analogues. The predicted binding behavior of the latter within two different previously crystallographically characterized protein-Axitinib binding sites (VEGFR2 kinase and ABL1 T315I gatekeeper mutant kinase), and an assessment of their suitability and anticipated shortcomings, are presented.

Keywords: AMBER; Conformation; Cytochrome P450; Rosetta; Sulfur hole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Axitinib / chemistry
  • Axitinib / pharmacology
  • Binding Sites
  • Models, Chemical*
  • Models, Molecular*
  • Molecular Conformation
  • Molecular Structure
  • Protein Binding
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • Receptors, Vascular Endothelial Growth Factor / chemistry
  • Sulfides / chemistry*


  • Sulfides
  • Axitinib
  • Receptors, Vascular Endothelial Growth Factor