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

Abstract

Epik is a computer program for predicting pK(a) 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 pK(a) 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.

Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity

“…24 To probe the importance of the sulfonamide moiety, phthalimide 12, also exemplified in the Banyu patent but without activity data, 21 was produced and found to have 10-fold lower activity than 7 and low partial efficacy, indicating that the sulfonamide is important for agonist activity but that replacement by other hydrogen bond acceptors is possible. The acyclic sulfonamide 13, containing a weakly acidic group (calculated pK a 7.7) 25 exhibited further reduced activity.…”

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

“…The aqueous solution ${\text{pK}}_{\mathrm{a}}$ values for the tail carboxylate moiety of αKG were predicted using Epik (Schrödinger Release 2015-3) 52 using default settings.…”

Theoretical Determination of the pK a Values of Betalamic Acid Related to the Free Radical Scavenger Capacity: Comparison Between Empirical and Quantum Chemical Methods

“…The Epik [33,34] method endorses the combination of two closely related linear free energy approaches based upon the Hammett equation for aromatic molecules and the Taft equation for aliphatic molecules to predict the pK a values of organic acids and bases. Hammett and Taft equations are intended to predict microscopic pK a values.…”