Journal of Computer-Aided Molecular Design

, Volume 21, Issue 12, pp 681–691

Epik: a software program for pKa prediction and protonation state generation for drug-like molecules

Authors

    • Schrödinger, LLC
  • Anuradha Cholleti
    • D. E. Shaw India Software, PL (DESIS)
  • Leah L. Frye
    • Schrödinger, LLC
  • Jeremy R. Greenwood
    • Schrödinger, LLC
  • Mathew R. Timlin
    • Schrödinger, LLC
  • Makoto Uchimaya
    • Schrödinger, LLC
Article

DOI: 10.1007/s10822-007-9133-z

Cite this article as:
Shelley, J.C., Cholleti, A., Frye, L.L. et al. J Comput Aided Mol Des (2007) 21: 681. doi:10.1007/s10822-007-9133-z

Abstract

Epik is a computer program for predicting pKa values for drug-like molecules. Epik can use this capability in combination with technology for tautomerization to adjust the protonation state of small drug-like molecules to automatically generate one or more of the most probable forms for use in further molecular modeling studies. Many medicinal chemicals can exchange protons with their environment, resulting in various ionization and tautomeric states, collectively known as protonation states. The protonation state of a drug can affect its solubility and membrane permeability. In modeling, the protonation state of a ligand will also affect which conformations are predicted for the molecule, as well as predictions for binding modes and ligand affinities based upon protein–ligand interactions. Despite the importance of the protonation state, many databases of candidate molecules used in drug development do not store reliable information on the most probable protonation states. Epik is sufficiently rapid and accurate to process large databases of drug-like molecules to provide this information. Several new technologies are employed. Extensions to the well-established Hammett and Taft approaches are used for pKa prediction, namely, mesomer standardization, charge cancellation, and charge spreading to make the predicted results reflect the nature of the molecule itself rather just for the particular Lewis structure used on input. In addition, a new iterative technology for generating, ranking and culling the generated protonation states is employed.

Keywords

Hammett and Taft (HT) equationsIonizationMesomerspKaProtonation stateTautomerizationTautomers

Supplementary material

10822_2007_9133_MOESM1_ESM.doc (202 kb)
Comparison between experimental and pKa values predicted by Epik for molecules listed in the drugbank with pKa values and SMILES patterns. Only predicted pKa values between 0.0 and 14 are reported except where the best matching pKa value exceeds 14 (nitrofurazone, mitomycin, and ethanol)

Copyright information

© Springer Science+Business Media B.V. 2007