Marina Shalaeva

ElogDoct:A tool for lipophilicity determination in drug discovery basic and neutral compounds

We present an RP-HPLC method for the determination of the octanol-water distribution coefficients at pH 7.4, as log values, for neutral and basic drugs, which combines ease of operation with high accuracy. The method is shown to work for a training set of 90 molecules comprised largely of drugs, and it was also applied to a test set of 10 proprietary compounds. This work expands the applicability of the method presented in our earlier report, for the determination of logP(oct) for neutral compounds (J. Med. Chem. 2000, 43, 2922-2928), and it offers the same general features but widens the scope. Generally, the method (i) is compound sparing (< or =1 mL of a 50-100 microg/mL solution needed), (ii) is insensitive to concentration and phase ratio effects observed in some shake-flask determinations, (iii) is amenable to rapid determinations (< or = 20 min on average), (iv) is insensitive to impurities, (v) possesses a wide lipophilicity range (>7 log units), and (vi) offers a good accuracy, (vii) an excellent reproducibility, (viii) and an excellent potential for automation. To the best of our knowledge, a similar performance, on a set of noncongeneric drugs, has not been previously reported. We refer to the value generated via this method as ElogD(oct).

Measurement of dissociation constants (pKa values) of organic compounds by multiplexed capillary electrophoresis using aqueous and cosolvent buffers

Evaluation of a multiplexed capillary electrophoresis (CE) method for pK(a) measurements of organic compounds, including low solubility compounds, is presented. The method is validated on a set of 105 diverse compounds, mostly drugs, and results are compared to literature values obtained from multiple references. Two versions of the instrument in two different labs were used to collect data over a period of 3 years and inter-laboratory and inter-instrument variations are discussed. Twenty-four point aqueous and mixed cosolvent buffer systems were employed to improve the accuracy of pK(a) measurements. It has been demonstrated that the method allows direct pK(a) measurements in aqueous buffers for many compounds of low solubility, often unattainable by other methods. The pK(a) measurements of compounds with extremely low solubility using multiplexed CE with methanol/water cosolvent buffers are presented.

In silico ADME prediction: data, models, facts and myths.

A critical review of a very recent work in the field of in silico ADME prediction is presented with emphasis on the work published during the period 2000-2002, and several other review articles are mentioned in order to offer a broader view of the field. We find that not much progress has been made in developing robust and predictive models, and that the lack of accurate data, together with the use of questionable modeling end-points, has greatly hindered the real progress in defining generally applicable models. Due to the largely empirical nature of QSAR/QSPR approaches, general and truly predictive models for complex phenomena, such as absorption and clearance, may still be chimeric. The development of local models for use within focused chemical series may be the most appropriate way of utilizing in silico ADME predictions, once experience and data have been gained on a given project and/or structural class.

Use of 3D Properties to Characterize Beyond Rule-of-5 Property Space for Passive Permeation

The application of conformationally dependent measures of size and polarity to characterize beyond rule-of-5 (Ro5) space for passive permeation was investigated. Specifically, radius of gyration, an alternative to molecular weight, and three-dimensional polar surface area and the generalized Born/surface area dehydration free energy, alternatives to hydrogen-bond donor and acceptor counts, were computed on models of the permeating conformations of over 35 000 molecules. The resulting guidelines for size and polarity, described by the 3D properties, should aid the design of Ro5 violators with passive permeability.

High Throughput Method for the Indirect Detection of Intramolecular Hydrogen Bonding

A supercritical fluid chromatography method was developed for the detection of intramolecular hydrogen bonds in pharmaceutically relevant molecules. The identification of compounds likely to form intramolecular hydrogen bonds is an important drug design consideration given the correlation of intramolecular hydrogen bonding with increased membrane permeability. The technique described here correlates chromatographic retention with the exposed polarity of a molecule. Molecules that can form an intramolecular hydrogen bond can hide their polarity and therefore exhibit lower retention than similar compounds that cannot. By use of a pairwise analysis strategy, intramolecular hydrogen bonds are identified within a test set of compounds with diverse topologies. The chromatographic results are confirmed by NMR chemical shift and temperature coefficient studies.

In silico prediction of ionization constants of drugs.

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.

Relationship between Passive Permeability and Molecular Polarity Using Block Relevance Analysis

EPSA is an experimental descriptor of molecular polarity obtained from chromatographic retention in supercritical fluid chromatography (SFC) systems, previously shown by Goetz et al. to correlate with passive permeability of cyclic peptides. The present study focuses on EPSA in relation to passive permeability of small molecules. We applied block relevance (BR) analysis to interpret the relative significance of mechanistic forces prevailing in EPSA. The BR analysis is a computational tool that allows the interpretation of the balance of intermolecular interactions governing systems such as the aforementioned chromatographic retention in EPSA. EPSA and passive permeability determined by Ralph Russ canine kidney cells (RRCK) or low efflux Madin Darby canine kidney cells (MDCK-LE) and human epithelial colorectal adenocarcinoma cells (Caco-2), studied on a data set of commercial drugs, indicated that EPSA is relevant in describing permeability of hydrophilic drugs (CLogP < 1). We then verified, on a data set of 1699 Rule of 5 compliant Pfizer compounds, that when CLogP < 1, a value of EPSA < 100 significantly increases the likelihood of high permeability.