The presentation will discuss how an existing molecule drawing tool (Marvin) and chemical database engine (JChem Base/Cartridge) are extended to handle generic features (R-group definitions, atom and bond lists, link nodes and larger repeating units, position and homology variation). It will be shown how Markush structures can be drawn and visualized in the Marvin sketcher and viewer, registered in JChem databases and their library space searched without the enumeration of library members. Different enumeration methods allow the analysis of Markush structures and libraries. These methods include full, partial and random enumerations as well as calculation of the library size. Furthermore, unique visualization techniques will be demonstrated on real-life examples that illustrate the relationship between Markush structures and the chemical structures contained in their libraries (involving substructures and enumerated structures).

The presentation will focus on the most recent developments (position variation, repeating units, homology variation), and further developments will be discussed towards full patent handling.

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Most importantly, it is prone to miss biologically relevant conformations. Representing flexible molecules on a continuous scale without the need of discrete sampling provides much higher degree of reliability and accuracy. But how can we address the complexity challenge and cope with the continuous flexibility within a manageable computational time frame?

A flexible 3D alignment method that overlays molecules by optimizing a potential function similar to the intersection of their molecular volumes has been developed. This method, based on the analytical representation of the conformational flexibility, is capable of aligning two or more chemical structures to very high accuracy. Nevertheless, the approach offers reasonable performance for drug-like molecules.

A generalization of the flexible conformational analysis apparatus enables the exploration of the entire conformational space of a molecule. The statistical analysis of this blurred spatial region provides a fairly low dimensional molecular descriptor which serves as the basis for a high throughput 3D virtual screening technique.

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The first part of the presentation gives an overview of the existing Markush functionalities, like the features of the combinatorial Markush structure handling, the existing enumeration methods and the Markush structure reduction. The Markush features are implemented as Markush database tables in two chemical databases of the ChemAxon, in the JChem Base and in the Instant JChem. Among the 2009 improvements worth to mention the repeating unit with repetition ranges, the homology groups and the identification of R-group definitions from reagent files.
Regarding the future the ChemAxon’s Markush development plans are related mostly to the patent claims.
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The major part of the presentation shows the development of the pipeline functionalities within ChemAxon that starts with the description of the available features. Among the most important functionalities the Standardizer, the Reactor, the Marvin applets, the MCS based clustering, the microspecies distribution, the IUPAC name and molecule converter or the burden eigenvalue descriptor are worth to mention. However the presentation puts the focus on the 2008 improvements, on the changes that happened in the versions from 1.2 to 1.4. The features that are emphasized in the presentation are as follows:

• Chemical Terms Calculator
• Canonicalization with Standardizer
• IUPAC naming components
• Changes in Reactor
• Clustering with LibMCS
• JChem Base insert
• JChem Database search
• Improved error reporting

On the closing slides of the presentation the planned components are discussed.
2008 Accelrys European User Group Meeting · 9-12 December 2008.
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The main topics of the presentation are as follows:

• Java API
• Marvin Applets for web applications
• .NET API over JNBridge
• Native .NET solution
• JChem Cartridge for Oracle
• SOAP interface
• AJAX GUI

The final slide of the presentation gives an overview about the software vendors that integrated ChemAxon softwares. For example the Pipeline Pilot, KNIME, Spotfire, Aureus and Integrity are mentioned among the most important vendors.
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Such systematic names reveal the presence of characteristic groups, like carboxylic acids and classes of compounds, like esters. Currently, IUPAC is designing precise rules to assign a unique preferred name to each compound, which can be useful, for instance, in the context of patents.

ChemAxon provides tools to generate names from structures, and to generate structures from names. In both cases, we strive to support both traditional and preferred IUPACnames.

236th ACS National Meeting & Exposition · August 17-21, 2008

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Traditional clustering methods are based on similarity scores. These techniques are highly efficient from a bare computational point of view but results are often hard to interpret, even by experts.

A clustering technique that results in highly intuitive grouping of structures can be introduced by the use of the concept of maximum common substructure (MCS).

8th International Conference on Chemical Structures (ICCS) · June 1-5, 2008

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After the introduction of the ChemAxon’s product line the presentation starts to give an overview about the products that implemented Pipeline Pilot: Marvin Sketch, Marvin View, the Calculator Plug-ins or Chemical Terms. Among the ChemAxon tools the JChem Base is emphasized as several features and interfaces were added to that. Most of the innovations improved the searching facility of the database manager through concentrated functionality. The next important development the presentation talks about is the canonicalization functionality of the Standardizer that is simple to use but it can handle complex tasks too. The virtual synthesis of the ChemAxon’s Reactor was updated with Pipeline Pilot solutions as well to make the tool more effective, flexible, smart and compatible. The Pipeline Pilot was implemented to the Instant JChem as well to create and update databases that can be intuitively searched and analyzed. On the last few slides there’s an overview about the plan of the current and future developments, the list of the available components and the ones that are planned to become a component.

2008 SciTegic Pipeline Pilot User Group Meeting, March 5-7, 2008
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The major problems with the IUPAC naming is discussed in the first part of the presentation. Among these issues you can read about the difficulties of using the rules to define the principal chain of a structure, the method of the dearomatization and the problems to name the bridged cyclic structures. A solution for this issue was implemented in ChemAxon’s Marvin family. In the evaluation part of the presentation you can find an overall comparison of the Marvin and its competing products including even the manual naming. Besides the Marvin family the IUPAC naming functionality can be used in other tools as well. For example it is implemented in the Marvin Sketch as an interactive, real-time naming function; the Instant JChem contains a batch naming feature etc.

American Chemical Society Spring meeting, March 25-29th, 2007
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On the first slides of the presentation you can read about the problems that belong to the topic of the Chemical Terms. The related questions are listed within four categories: virtual reactions, filtering, pharmacophore mapping and random evolutionary de Novo drug design. The following slides give the answers for these questions presenting the development of the Chemical Terms functionality to solve the above mentioned chemical problems. Afterwards you can read about the Chemical Terms’ function examples including substructure matching, chemical calculations, the calculation of returning molecules and combining functions in the tools. In the end of this part of the presentation the Chemical Terms Editor is introduced in a few words.
The major part of the presentation focuses on the ChemAxon applications that the Chemical Terms functionality is built in. The Instant JChem, the filters of the Pipeline Pilot, the Reactor, the Metabolizer are mentioned in this section. Finally an overview of the upcoming Chemical Terms features is discussed in three major groups: simplified syntax, simplified editing and new functionalities.

American Chemical Society Spring meeting, March 25-29th, 2007
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Moreover, current computational tools used for structure determination, including force-fields and quantum chemical methods, require a complete set of initial 3D coordinates. The efficiency of 3D structure based HTS (high throughput screening) tools also can be enhanced by employing conformational analysis to yield multiple valid structures.

Our approach utilizes a composition of several methods ranging from pure rule based1, multi dimensional distance geometry method2 to stored substructure lookup features in a flexible software framework. The actual implementation is a highly portable JAVA software, which fits in a broad scale of applications: it can be used in small web drawing applets3 as well as a standalone database processing component.

The coordinate determination process is characteristically a “divide and conquer” approach: the structure is composed of fragments, which are joined together. From the available fragment conformers, the conformers of the joined structures can be generated during the fuse step. The fragment conformers are generated either through further fragmentation or with an elemental structure/conformer prediction method, consequently the conformational analysis is an inherent part of the building process (in contrast with methods proceeding from 3D initial structures4). The novelty of our approach lies in the diversity of the utilized elemental
methods and the arisen scalability options.

1st European Chemistry Congress, Budapest, Hungary, 27-31 August, 2006.

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Apart from the naturally occurring mesomeric and tautomeric issues, chemical compounds are rarely neutral and pure, thus counterions and solvents might appear in the chemical structure files making the identification even more problematic.

ChemAxon1 developed Standardizer, a Java-based software tool for the batch conversion of chemical structures according to a standard defined by the chemical database administrator.

25th Chinese Chemical Society Congress, 11-15, July 2006

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It also has to be admitted, that these software work well, they provide good image quality, are rich in features and do not show stability or performance problems. So why implement “yet another molecular structure visualization software”?

ChemAxon already has an active chemical editor and viewer development as well as a plugin technology for property prediction. From our users and own experience we felt that none of the existing visualization tools provided all of the key features in one device and that some functionalities are not available, particularly;

• web-enabled high quality rendering
• managing very large complexes
• all types of common molecular surfaces are available
• molecular properties are mapped on surfaces
• interactive monitors and controls
• platform independent
• available as programmers toolkit (Java API)
• professional support

MarvinSpace, ChemAxon’s new 3D molecule visualization and modeling software aims to achieve a wide spectrum of functions combined with near print quality interactive rendering in a platform independent solution. MarvinSpace should be useful for content providers, online publishers, public internet databases, chemoinformatians, medicinal chemists, modelers and biochemists.

InfoTechPharma, 13 – 16 March 2006

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To automate the virtual synthesis process, we have moved the expertise intensive parts from the compound library design phase to the reaction library design phase. ChemAxon is building an in silico reaction library containing important preparative transformations, where each reaction definition contains a generic transformation scheme and additional rules to handle the various starting compounds according to the corresponding chemo-, regio-, and stereoselectivity issues. Having well designed reaction definitions in hand, our software tool is able to generate synthetically feasible compound libraries with minimal effort in the enumeration phase.

J. Chem. Inf. Model. 2006, 46, 563-568.
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Our approach utilize a composition of several methods ranging from pure rule based multi dimensional distance geometry method to data based stored substructure lookup features in a flexible software framework. The actual implementation is a highly portable JAVA software, which fits a broad scale of applications: it is used in small web drawing applets as well as standalone database processing component.

The coordinate determination process can be best characterized by the “divide and conquer” approach: the structure is composed of fragments, which are joined together. From the available fragment conformers the conformers of the joined structures can be generated during the fusing step. The fragment conformers are generated either through further fragmentation or with an elemental structure/conformer prediction method, consequently the conformational analysis is an inherent part of the building process. The novelty of our approach lies in the diversity of utilized such elemental methods and the arisen scalability options.

7th International Conference on Chemical Structures, 5-9 June 2005
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The mathematical foundation is too complicated to solve and there is no standard method to describe the valuable knowledge of experienced synthetic chemists in exact formulas, which could be evaluated by computers. In the scope of this presentation, we will introduce ChemAxon’s approach for modeling reactions, a software component able to generate synthetically feasible products and some interesting applications of this technology.

The number of known compounds is permanently growing, currently, more than 24 millions are registered in the Chemical Abstracts

1. But this is only a teeny-weeny part of the realizable molecules. The estimated number of realizable molecules is so high due to the wonderful variability of organic elements
2. Even much higher than the number of atoms in the Universe, which can be estimated from its mass
3. Our current technology does not enable us to synthesize and test most of the possible compounds in the foreseeable future, thus, we need something much faster and cheaper than preparative or combinatorial synthesis helping us to select those few molecules worth to be synthesized.

9th Annual InfoTechPharma® Conference, 15-16 March, 2005.

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On one end of the spectrum virtual screening techniques, for instance, are fast and guarantee the availability of virtual hits for in vitro tests. However, the set of available chemicals is limited (10 000 000 is probably a good upper estimation for the number of known chemicals) and this implies a limited usability of virtual screening.

Towards the other end of the spectrum of discovery tools de novo drug design methods try to alleviate the problem of a finite compound space by suggesting novel molecular structures. Often, these are assembled by linking small molecular fragments in a procedure which is more or less chemically unaware. As a consequence the synthetic accesibility of de novo designed ligands is often a problem.

A method, which combines advantages of virtual screening with advantages of de novo design while eliminating their disadvantages has been implemented. This method deploys virtual screening over an ever growing space of virtual compounds that are likely to be synthetically accessible. To achieve this, commercially available chemical structures are combined by smart chemical reactions . These, unlike generic reaction equations that generate all possible products that are topologically relevant, are capable of eliminating products that are unlikely to be accessible via chemical synthesis.

In addition to synthetic accessibility there is another advantage of this method: no design is involved during structure generation. Consequently structures will be diverse both chemically and biologically and they can be screened for various targets simultaneously or at a later time so no potential lead is lost.

The applicability and efficiency of the method will be demonstrated with various examples.

Workshop on Chemical Information, July 2, Lausanne, Switzerland
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The micro ionization constant is obtained from empirically calculated partial charge distribution of a molecule. The calculation of micro partition coefficient, logD , is based on atomic fragment values. Micro partition coefficient of ionized microspecies, also calculated from atomic fragment values. The ionic strength and zwitterionic effect on log is also included in the log calculation.

227th ACS National Meeting, Anaheim, California · March 28 – April 1, 2004

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Huge virtual libraries can be generated by computer programs, but the quality of the results depends on technology of reaction modeling. It is a hard nut to crack, since preparative chemistry is not an abstract science and theory often fails in practice.

The ideal virtual reaction library contains a few hundred generic reactions equipping chemists with classified preparative transformations. Furthermore, the ideal virtual reactions are specific to generate chemically feasible products from each individual compound. So, how can a generic reaction be specific?

227th ACS National Meeting · March 28 – April 1, 2004 · Anaheim, California

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We focus on topological pharmacophore similarity based search where only a set of known active 2D structures is known. The pharmacophores of these structures are analysed by perceiving the pharmacophoric characteristic of each individual atom. Pharmacophore patterns are transformed into a topological cross correlation histogram. These correlation histograms are molecular descriptors that represent the pharmacophoric character of structures in a mathematically tractable form. Proximities (metrics) like the Euclidean distance and the Tanimoto coefficient are applied to estimate the dissimilarity between two such descriptors. The canonic formulae of the proximities are extended with weights and other parameters to help bias the metrics behaviour when comparing two compounds. Parameters are optimized in an automated training process that uses a subset of the target library and a subset of the known active structures. The optimized proximities are then passed on to an independent validation stage, which evaluates by calculating the enrichment ratio achieved within the virtual screening process.

Optimized virtual screening is capable of reducing the size of the ‘haystack’ by another order of magnitude (in some cases an even higher reduction is achieved) and it can also lead to scaffold hopping. The method is generic enough to adapt to other molecular descriptors and metrics. The efficiency of the method and cross-validated results will be presented.

eCheminformatics 2003, November 10-15, 2003
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However, automatic, ‘batch’ processes cannot be applied on a large number of molecules if they imply human intervention. Studies, like QSAR, pharamacophore analysis, reaction prediction might need full, complete 3D information for the compounds of interest. The widespread tools used for structure determination (force-fields or quantum chemical methods) even require a complete set of initial 3D coordinates.

Our approach intends on generating globally valid set of 3D coordinates for small and medium sized molecules, based on local structural criteria. Over against iterative, backtrack based structure predicting algorithms, our method is capable of satisfying partially inconsistent requirements. Such situations are common for structures holding polycyclic, rigid details.

Goals mentioned above can be achieved using coordinates interpreted in a space with a Minkowski metric. Our coordinate assignment process is divided into the following parts: (I) Automatic generation of distance criteria based on chemically relevant local properties, such as bond stretches, bond angles, dihedral angles, etc. (II) Multi-dimensional coordinate assignment which fulfills all the criteria. (III) Geometry optimization using a force field extended to the multi-dimensional Minkowski space. The optimization eliminates the over-3D components and yields the 3D coordinates.

Journal of Molecular Structure (Theochem), 666-667 (2003) 51-59
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In the starting part of the presentation the common marks, properties of two molecules are described. Molecular structures are encoded into molecular descriptors, e.g. fingerprints which can be handled numerically. That led to the method of virtual screening using these fingerprints. Fuzzy pharmacophore fingerprints offer a way to enhance the performance of screening and the introduction of tunable parameters in dissimilarity metrics can increase the performance too. In the second part of the presentation the optimalization of these parameters are discussed including the optimalization goal, the hypothesis, the examples of the hypothesis and the results. The pharmacophore perception is implemented within the ChemAxon’s JChem software tools.

Drug Discovery Technology, Boston, USA, August 10-15, 2003
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Modeling chemical structures is a well established approach which has proved itself in practice, however there are many hazards on the road to virtual reaction processing. Specific virtual reactions work well with specific compounds but they are not usable for batch processing large molecule libraries. On the other hand, the application of generic reaction equations needs permanent manual control to eliminate chemically meaningless or not synthesizable products.

An ideal chemical transformation rule needs to be generic to apply to compound libraries yet specific so as to be able to process only chemically feasible transformations.

Drug Discovery Technology, Boston, USA, August 10-15, 2003

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The lower is the pKa of the free amine of the mono-Boc species the higher is the yield of the mono-boc product. Isolated diamines can be reacted according to the following rule: in acidic medium the lower in neutral medium the greater pKa valued nitrogen can be protected with acceptable selectivity. Alkyl chain longer than 3 carbons reduces the favorable neighborhood effect. Over 8 pKa difference value the amines can be reacted selectively in chemical reactions.

There are certain problems which this model overlooks:

1. Stability of the protected amines vs. pH and temperature
2. Stability of the heterocyclic systems vs. pH and temperature

The bulky Boc O is very sensitive to the steric hindrance, which is confirmed by regioselectivity of the Boc-protection and the sensitivity of the reaction velocity to the steric hindrance.

Advancing Library Design and Organic Synthesis, La Jolla, California, February 24-27, 2003
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The presentation mentions among the major advantages of the Marvin that it is faster than the similar applets because it is modularized, it can handle many file formats and it is highly configurable and controllable. After the general introduction to the Marvin two products of the family is described thoroughly. The first is the MarvinSketch which is a tool for drawing chemical structures. The other is MarvinView that is a 2D/3D viewer that can display a molecule, or many molecules in a table.

The 3rd International Electronic Conference on Synthetic Organic Chemistry (ECSOC-3)
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In the introduction the complex chemical web application’s technology is described: it combines the elements of web technology, database technology and chemical software technology. The complexity of the problem requires new directions from the ChemAxon: creating Java based softwares. It is compatible with almost all operation systems, web servers and database servers too.

The 5th International Conference on Chemical Structures (5th ICCS), Noordwijkerhout, June 6-10, 1999
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