Tautomerism and Its Applications in Drug Design
Summary
Tautomerism is the reversible interconversion between constitutional isomers that differ by the position of a proton and the arrangement of π-electrons. In the context of drug design, tautomerism can markedly influence the physicochemical properties, binding affinity, selectivity and metabolic fate of small-molecule therapeutics. Many bioactive compounds populate multiple tautomeric states under physiological conditions, altering patterns of hydrogen bonding, lipophilicity and electronic distribution. This variability must be accounted for when modelling protein–ligand interactions, predicting absorption, distribution, metabolism and excretion (ADME) profiles or optimising lead compounds. Experimental approaches such as NMR spectroscopy, X-ray crystallography and UV–visible spectroscopy can characterise dominant tautomers in solution or in the solid state, while quantum-chemical calculations and enhanced sampling techniques enable estimation of relative free energies of tautomeric pairs. Recent advances in machine learning and alchemical free energy methods offer the prospect of rapid, accurate prediction of tautomer populations in complex environments. By integrating detailed thermodynamic and kinetic data on prototropic shifts with structure-based design, researchers can rationally favour a desired tautomeric form, stabilise elusive species through metal coordination or exploit dynamic intramolecular hydrogen‐bonding networks to confer “chameleonic” behaviour. Such strategies underpin the development of next-generation therapeutics with optimised potency, selectivity and pharmacokinetic profiles.
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Technical terms
Tautomerism: Equilibrium between structural isomers that differ by proton position and bonding arrangement.
Keto-enol tautomerism: A specific proton transfer between a carbonyl (keto) and an adjacent alkene–alcohol (enol) form.
Intramolecular hydrogen bond (IHB): A hydrogen bond formed within a single molecule, stabilising particular tautomers or conformers.
Free energy calculations: Computational methods that estimate the relative stability and population of molecular states in solution or enzymes.
Prototropic shift: The intramolecular transfer of a proton that effects tautomeric interconversion.
References
- Keto-enol tautomerism in the development of new drugs. Frontiers in Chemical Biology (2024).
- Competitive Intramolecular Hydrogen Bonding: Offering Molecules a Choice. ChemPlusChem (2024).
- Investigation on the stability of the Enol Tautomer of Favipiravir and its derivatives by DFT, QTAIM, NBO, NLO and 1H-NMR. Journal of Taibah University for Science (2023).
- Stabilization of an elusive tautomer by metal coordination. Acta Crystallographica Section C: Structural Chemistry (2021).
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