In Silico Prediction of Ionization Constants of Drugs

Abstract

Most pharmacologically active molecules contain one or more ionizing groups, and it is well-known that knowledge of the ionization state of a drug, indicated by the pKa value, is critical for understanding many properties important to the drug discovery and development process. The ionization state of a compound directly influences such important pharmaceutical characteristics as aqueous solubility, permeability, crystal structure, etc. Tremendous advances have been made in the field of experimental determination of pKa, in terms of both quantity/speed and quality/accuracy. However, there still remains a need for accurate in silico predictions of pKa both to estimate this parameter for virtual compounds and to focus screening efforts of real compounds. The computer program SPARC (SPARC Performs Automated Reasoning in Chemistry) was used to predict the ionization state of a drug. This program has been developed based on the solid physical chemistry of reactivity models and applied to successfully predict numerous physical properties as well as chemical reactivity parameters. SPARC predicts both macroscopic and microscopic pKa values strictly from molecular structure. In this paper, we describe the details of the SPARC reactivity computational methods and its performance on predicting the pKa values of known drugs as well as Pfizer internal discovery/development compounds. A high correlation (r2=0.92) between experimental and the SPARC calculated pKa values was obtained with root-mean-square error (RMSE) of 0.78 log unit for a set of 123 compounds including many known drugs. For a set of 537 compounds from the Pfizer internal dataset, correlation coefficient r2=0.80 and RMSE=1.05 were obtained.

Predicting Clearance Mechanism in Drug Discovery: Extended Clearance Classification System (ECCS)

“…5c). As discussed earlier, ionization state is the key molecular property defining the ADME characteristics and is easily obtained from the chemical structure using either in silico tools or in vitro tools [178,179]. Finally, unlike BCS and BDDCS, ECCS cannot be applied for biowaivers purposes as it does not consider solubility and formulation aspects of oral absorption.…”

Modern methods for estimation of ionization constants of organic compounds in solution

“…As applied to calculation of pK a 's, an important condition for effective use of QSPR methods is accessibility of extensive databases and literature compilations on experimental pK a values [20,[195][196][197][198] for constructing correlations and estimating the prediction accuracy. Unfortunately, sets of reliable experimental data for some classes of organic compounds are quite limited, especially for nonaqueous media [195], which is a serious obstacle to efficient application of QSPR.…”

“…It is based on the linear free energy relationship principle and perturbational molecular orbital (PMO) theory and is briefly described in [20,33]. A compound under study is considered to consist of reaction center, acting substituents, and bridging atoms connecting the reaction center with substituents.…”

“…The quantity pK a is among physicochemical parameters determining the set of principal pharmacodynamic and pharmacokinetic parameters of molecules (so-called ADMET profile). Therefore, this parameter of biologically active substances in aqueous media is necessary for prediction of pharmacological properties [19][20][21].…”

Simultaneous determination of dihydroxybenzene and phenylenediamine positional isomers using capillary zone electrophoresis coupled with amperometric detection

“…The pH value of running buffer is the most important factor in CZE to get a satisfactory separation efficiency of positional isomers. Usually, the pH value of running buffer should be as possible as close to the pK a values of the positional isomers, at which the largest charge-mass ratio difference could be obtained [10][11][12][13]. For example, because the pK a values of o-, m-, and p-phenylenediamine isomers are 4.52, 5.64 and 6.04, respectively, the best pH value in CZE for these isomers separation is about 5.8.…”