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

Computational assessment of thioether isosteres.

Author information

1
Department of Chemistry & Chemical Biology, Rutgers The State University of New Jersey, 610 Taylor Rd., Piscataway, NJ 08854 USA.
2
Department of Chemistry & Biochemistry, Swarthmore College, 500 College Ave., Swarthmore, PA 19081 USA.
3
Department of Chemistry & Chemical Biology, Rutgers The State University of New Jersey, 610 Taylor Rd., Piscataway, NJ 08854 USA. Electronic address: spencer.knapp@rutgers.edu.

Abstract

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

PMID:
29414047
DOI:
10.1016/j.jmgm.2018.01.018

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