Physico-chemical property predictors

Calculations and predictions of essential physico-chemical characteristics

This set of tools offers fast, accurate and trainable predictions of basic physicochemical properties such as logS, logP, logD, pKa. In addition, robust prediction of NMR spectra of molecules that facilitates structure interpretation and elucidation is also available. Besides the predictors, this collection contains the technology to generate stereoisomers and tautomers of the input structures according to user-specified limits.

Solubility Predictor

Aqueous solubility is one of the most important factors in drug discovery. As solubility plays a key role in the absorption and distribution of molecules it is always subject to optimization. Appropriate prediction of the solubility can be used to predict oral bioavailability as well as to avoid erratic assay results, hence properly designed soluble compounds can be formulated easier and in a shorter development time. A robust solubility prediction solution is therefore of crucial importance in the early phase of the discovery process.

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Structure based prediction

ChemAxon’s novel aqueous solubility predictor is based on the topology of the input molecules. It not only predicts the intrinsic water solubility of compounds, but in combination with the pKa and Microspecies prediction engine it also calculates pH dependence as well as solubility at a desired pH level.

Quantitative or qualitative estimates

The calculation can aim to giving back quantitative solubility values in either logS, mg/mL or mol/L units.

In case only a rough estimate is needed, the algorithm can also simply predict a qualitative measure of the water solubility of a compound.

Microspecies distribution

Accessibility

The Solubility plugin can be used in Marvin Sketch for single compounds, as well as via command line with cxcalc for batch processing. As any other ChemAxon calculation and prediction, it can also be accessed with Chemical Terms functions which allows users to carry out calculations in Instant JChem or other JChem based products.

The Protonation bundle

Very often drug-like molecules are weak acids or bases with multiple low-energy ionization states. The reliable prediction of these states is essential during pharmaceutical research, or the characterization of various organic and inorganic chemical processes. The Protonation bundle contains a robust toolkit to predict protonation related molecular properties.

Predicting the pKa

The pKa plugin predicts the pKa values of all proton receiving or donating atoms in a molecula. The prediction is done on the basis of the partial charge distribution calculated on the fly. The plugin provides an efficient and robust way to locate the most acidic and basic sites in a molecule under user-defined conditions.

Distribution of estimation error

Microspecies plugin

The Microspecies plugin allows the determination of the major protonation form at a specified pH. The major mirospecies can be predicted based on the tautomeric form defined by the user, or the plugin can automatically generate the dominant tautomer and use it as a basis for the calculation.

Microspecies distribution

Isoelectric point

The isoelectric point, i.e. the particular pH, at which the net charge of an ionizable molecule is zero can be also determined. The Isoelectric point plugin can also calculate the pH-dependent net charge distribution of the subject molecules.

Isoelectric Point

Partitioning bundle

The accurate prediction of the partition coefficients is an essential component in ADME prediction processes. ChemAxon’s technology helps researchers to calculate not only the octanol-water partition coefficients for single protonation state (logP) of a compound, but also the pH-dependent logD values.

The Hydrophil-lipophil balance (HLB) number is an important measure of how hydrophil or lipophil a molecule is. Having a quantitative measure of this chemical property is becoming important in chemical systems, that contain components of different lipophilicity (e.g.: lipid-based drug delivery). ChemAxon’s HLB predictor is able to calculate the HLB number of a chemical compound.

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logP and logD predictor

Both logP and logD predictions are based on a modified version of the method of Viswanadhan et al. , where the predicted partition coefficients are composed of the molecules’ atomic increments. The applied modifications include the redefinition of selected atom types to accommodate electron delocalization (in particular for sulfur, carbon, nitrogen, and metal atoms), and the addition of contributions of ionic forms.

The logP value of zwitterions is calculated from the logD at the isoelectric point. Also, the effect of hydrogen bonds on logP is considered if the formation of a six membered ring between suitable donor and acceptor atoms can take place. As the logD values are pH-dependent, the logD calculation relies on the pKa prediction process. Besides the default training data sets the logP-logD calculation plugin allows you to create and apply local models based on in-house experimental datasets.

LogP representation

Hydrophil-lipophil balance (HLB) predictor

The HLB predictor provides different methods for calculating the HLB number. All these methods work based on identifying different molecular fragments, to which hydrophilor lipophil contributions are assigned.

The classical Griffin and Davies methods were both extended to handle a wider chemical space. These two methods were combined in a ChemAxon HLB model to get optimal results.

hydrophil-lipohpil-predictor

Isomers bundle

Most compound collections (corporate databases, screening libraries, compound-provider catalogs) are comprised of 2D structures with incomplete indications of stereochemistry or tautomeric state. This inevitably leads to ambiguous stereochemistry or tautomerisation when these structures are converted to 3D. The enumeration of tautomers and stereoisomers of molecules is essential for virtual screening applications such as docking, 3D-searching or 3D-QSAR facilitating drug discovery and development processes.

Generating tautomers

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Many readily available libraries provide ligand structures in familiar tautomeric forms. These forms may not be highly populated under biological conditions, and are therefore inappropriate for property prediction or virtual screening experiments.

Tautomer search types

ChemAxon’s tautomer enumerator generates all tautomeric forms of the given molecule and allows users to choose the most suitable for a given study.

Besides generating particular tautomers, the application is capable of creating generic tautomeric forms that allow searching for duplicate structures.

Generic tautomers

Stereoisomers

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A substantial step towards the understanding of the physical, chemical, or biological properties of a molecule is to study and to analyze its 3D conformations. The exploration of the configurational space of a molecule and the analysis of the various isomers a molecule can adopt is therefore of great importance. Besides the topology, a major shape determining features is stereochemistry. Chirality plays a major role in many areas of chemistry, as enantiomers often exhibit quite different physical, chemical, and biological properties. The Stereoisomer Plugin produces all possible stereoisomers of a given compound. It handles both tetrahedral and double bond stereogenic centers. During the enumeration process energetically impossible conformations can be filtered out.

NMR Predictor

The prediction of NMR spectra can play a very important role in structure validation and elucidation of molecules. ChemAxon’s NMR Predictor can predict both 1H and 13C NMR spectra of organic compounds.

NMR spectrum prediction for organic compounds

The NMR Predictor application is able to predict NMR spectra for standard organic molecules containing the most frequent atoms (H, C, N, O, F, Cl, Br, I, P, S, Si, Se, B, Sn, Ge, Te, As). Chemical shifts are estimated by a mixed HOSE and linear model based on a topological description scheme. They are relative to the chemical shift of tetramethylsilane (δ(TMS)=0 ppm).

Spectrum view

Get detailed NMR spectrum information

The interface of the NMR Predictor provides the details of the predicted spectrum for browsing in separate panels.

These panels display among others chemical shifts, net intensities, spin-spin coupling constants as well as the quality of the prediction for a given atom.

Quality table

Rich spectrum visualization options

The NMR Predictor tool includes rich spectrum viewer functionality including atom-to-peak assignment, flexible zooming, realistic and line spectrum representation, as well as smart multiplet selection that allows the separation of overlapping multiplets.

NMR representation

In addition, a dedicated spectrum preview window makes it easier to browse the NMR spectrum.

Proton coupling

Import and export spectra

Predicted spectra can be exported to JCAMP-DX (.jdx) spectrum files. Besides this special format, spectra can be exported to PDF files, or simply copy-pasted as images. The dedicated NMR Spectrum Viewer of the application can be used for loading and browsing .jdx files.

NMR prediction via various interfaces

The NMR prediction functionality is accessible via Marvin Sketch’s graphical user interface, as well as in command line via cxcalc. The NMR Predictor can also be applied within a web browser through the Marvin applet.

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