Computational assessment of thioether isosteres.

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Structural Biology

Background:

• Thioethers are susceptible to metabolic oxidation, limiting their use in drug development.
• Replacing the sulfur atom in thioethers with alternative linkers is a strategy to enhance metabolic stability.
• Understanding the structural and electronic properties of these replacements is crucial for designing stable drug analogues.

Purpose of the Study:

• To computationally evaluate various one-atom or two-atom linkers as replacements for the sulfur atom in thioethers.
• To assess the potential of these novel thioether isosteres in medicinal chemistry applications.
• To predict the binding behavior of designed Axitinib analogues with modified thioether linkages in key kinase targets.

Main Methods:

• Utilized ab initio calculations to analyze the structural and electronic performance of proposed thioether isosteric groups.
• Computationally evaluated four specific linkers as substructures within Axitinib analogues.
• Predicted the binding interactions of these analogues with VEGFR2 kinase and ABL1 T315I gatekeeper mutant kinase using computational modeling.

Main Results:

• Ab initio calculations provided insights into the structural and electronic properties of various sulfur replacements.
• Four novel thioether isosteres were evaluated as potential components of Axitinib analogues.
• Predicted binding behaviors of Axitinib analogues with modified linkers in VEGFR2 and ABL1 T315I kinase active sites were presented.

Conclusions:

• The study offers a computational framework for designing metabolically stable thioether-containing drug candidates.
• Novel thioether isosteres show promise for improving the pharmacokinetic profiles of drugs like Axitinib.
• Computational predictions guide the selection of optimal linkers for enhanced binding and reduced metabolic liability in kinase inhibitors.