Modulating intramolecular chalcogen bonds in aromatic (thio)(seleno)phene-based derivatives

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Drug Design

Background:

• Intramolecular interactions are vital for controlling molecular conformation in drug discovery.
• Chalcogen interactions have been observed in ligands targeting the GK-GKRP protein.
• Understanding these interactions aids in developing more effective therapeutics.

Purpose of the Study:

• To investigate the potential of intramolecular chalcogen interactions, specifically through selenium, in drug design.
• To evaluate the strength of selenium-mediated interactions compared to other chalcogen interactions.
• To assess the role of carbon backbone flexibility in ligand conformational stability.

Main Methods:

• Computational modeling and analysis of ligand-protein interactions.
• Focus on intramolecular chalcogen bonds involving selenium.
• Structure-activity relationship analysis considering backbone rigidity.

Main Results:

• Intramolecular interactions involving selenium form significantly stronger bonds than previously observed chalcogen interactions.
• Selenium-mediated interactions show high promise for conformational control in drug candidates.
• Ligand carbon backbone flexibility directly correlates with conformational stability and binding efficacy.

Conclusions:

• Selenium-based intramolecular interactions represent a potent strategy for enhancing drug design.
• Optimizing ligand backbone flexibility is essential for maximizing the effectiveness of these interactions.
• This research provides a foundation for developing novel therapeutics targeting GK-GKRP and similar proteins.