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Maleic hydrazide is commonly represented as a dione, shown in the top left corner of the above figure. However, the dione tautomerizes to the more stable alcohol shown here, which subsequently undergoes deprotonation in water. Because Epik iteratively tautomerizes and ionizes, it is able to correctly identify this acidic hydrogen and remove it from the output structure. Epik predicts its pK_a to be 5.28, which is in good agreement with the experimentally determined pK_a of 5.67.

Epik: Rapid and robust pK_a predictions

Combining the proven reliability of Hammett and Taft methods with powerful tautomerization tools, Epik is the program of choice for accurate enumeration of ligand protonation states in biological conditions.

The Advantages of Empirical pK_a Prediction

Proper treatment of ligand protonation states is essential to lead discovery. The pK_a's of a drug's various functional groups play a critical role in determining its bioavailability and pharmacokinetic profile, while virtual screening software relies on correctly protonated structures in order to perceive the discrete interactions that drive ligand binding. However, many readily available libraries provide ligand structures in familiar tautomeric forms with all functional groups neutralized. These forms may not be highly populated under biological conditions, and are therefore inappropriate for property prediction or virtual screening experiments.

Epik provides a time-tested solution to these problems, designed specifically to work within the context of contemporary drug discovery workflows. Using Hammett and Taft methods in conjunction with ionization and tautomerization tools, Epik is able to rapidly and reliably predict pK_a values and return all chemically sensible structures.

Works to Cite

Shelley, J. C.; Cholleti, A.; Frye, L. L.; Greenwood, J. R.; Timlin M. R.; Uchiyama, M., "Epik: a software program for pKa prediction and protonation state generation for druglike molecules," J. Comput. Aided Mol. Des., 2007, 21, 681–691.

Greenwood, J. R.; Calkins, D.; Sullivan, A. P.; Shelley, J. C., "Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution," J. Comput. Aided Mol. Des., 2010, 24, 591-604.

Park, M.; Gao, C.; Stern, H.A., “Estimating binding affinities by docking/scoring methods using variable protonation states,” Proteins, 2010, 79, 1, 304-314.

Please note that the pKa and tautomeric databases provided with Epik are copyrighted material, and should not be extracted, reproduced, or used outside of the context of Epik or LigPrep licensed calculations.