Tautomerism, Hammett sigma, and QSAR

Area of Science:

• Medicinal Chemistry
• Physical Chemistry
• Computational Chemistry

Background:

• Tautomeric equilibria are crucial in understanding drug-receptor interactions.
• The influence of tautomeric forms on quantitative structure-activity relationships (QSAR) remains an area of investigation.
• Equilibrium-based models are frequently employed in drug design.

Purpose of the Study:

• To investigate the impact of tautomeric equilibria on the observed potency of compounds.
• To analyze how tautomeric equilibria affect the correlation between potency and electronic parameters like Hammett sigma.
• To determine the conditions under which tautomeric equilibria can induce a correlation between potency and electronic parameters.

Main Methods:

• Utilized equilibrium model-based equations to analyze tautomeric behavior.
• Examined the relationship between compound concentration in solution and tautomer prevalence.
• Assessed the correlation between observed potency and Hammett sigma values under varying tautomeric conditions.

Main Results:

• Tautomeric equilibria show minimal effect on observed potency if a tautomer comprises at least 50% of the compound in solution.
• Tautomeric equilibria can either strengthen or weaken the correlation between potency and Hammett sigma.
• A correlation between potency and Hammett sigma can emerge due to tautomeric equilibria, even without a direct correlation in binding.

Conclusions:

• The prevalence of a specific tautomer in solution is a key factor in determining its effect on observed potency.
• Tautomeric equilibria represent a significant consideration in QSAR studies, potentially explaining observed correlations with electronic parameters.
• Understanding tautomeric influences is vital for accurate drug design and optimization, particularly when relying on electronic descriptors.