eCombiChem Leads

In silico Library Enumeration of Synthetically Feasible Libraries

Virtual synthesis programs are not yet widely used by synthetic chemists and many may doubt that such approaches can match the skills of the experienced chemist.  Nevertheless ChemAxon have created a Java-based Reactor system to process reactions according to rules captured in the syntax of the Chemical Terms language for reactivity, selectivity, and side reaction exclusion.  Using such a system, discovery enumeration is significantly extended beyond a desired product library to create instead a reaction library, which has taken into account availability of starting compounds, experimental conditions, and prior available chemistry reaction knowledge on reaction types and their chemo-, regio-, and stereoselectivity issues.  A combinatorial synthesis library of a million such reactions can currently be built using several hours of CPU.

Oxford-based Inhibox, founded by Graham Richards, chairman of Chemistry at the University of Oxford, and headed by CEO Paul Finn, who pioneered the implementation of virtual screening methodologies for Pfizer at Sandwich, have been developing novel computational discovery methods and created Scopius, a very large database of chemical structures for drug discovery. Inhibox are using ChemAxon’s Reactor software to establish optimum conditions to give 'synthetically accessible' libraries with favourable properties for their research, and to create a reaction service, with workflows to create de novo libraries for client projects. “The core functionality to enumerate focused de novo type libraries in Oracle for a number of organic transformations is already available”, according to lead developer Dan Butler at Inhibox who continued “In a nutshell what we are attempting to do with Reactor is create a service which will primarily allow creation of focused de novo approach libraries and secondarily, exhaustive sets, for organic transformations that have (a) a reasonable set of suitable reactants in our commercial database and thus a tangible starting point and (b) are well defined reactions in the literature. In addition the Chemical Terms functionality of Reactor may help us create more accurate product sets. Overall this is quite a large undertaking in many respects, not least of which are the amount of organic transformations available to implement!”

Dan Butler will be joined in Oxford by ChemAxon’s CTO and virtual synthesis expert György Pirok to reveal the results of this work for the first time at the eCheminfo Drug Discovery Training Week at Oxford University (3-7 July 2006). Attendees to their workshop will be able to use provided software to create virtual reaction libraries and to work with the workshop leaders to establish optimum conditions to give 'synthetically accessible' libraries with favourable properties for their research. Dr. Pirok commented that “Currently we are developing a GUI so that synthetic chemists, who are not familiar with programming or command line tools, will be able to generate these reaction libraries. This GUI also contains an editor for modifying existing reactions or creating new ones. Workshop participants in Oxford will be one of the first set of users trying the new desktop Reactor application and GUI, and will get to try the newest features not previously released.  We will try to create new selective reactions and libraries together during the workshop, that will be of relevance to participants’ interests.”

Barry Hardy
eCheminfo Community of Practice

Training eCheminfo meeting workshop conference management chemistry Life Sciences Pharma Drug Discovery Drug Design Synthetic Chemistry Organic Chemistry Virtual Synthesis Innovation Informatics cheminformatics chemoinformatics IT Molecular Modeling Molecular Modelling events

Autumn InterAction Meeting Program on Drug Discovery & Development

I summarise below the list of sessions with over 100 top speakers and discussion leaders for the program listing for the upcoming Autumn InterAction Meetings taking place in Philadelphia and Basel. Please add a traceback or link for other like-minded folk to find!

I also provide an electronic brochure for download here for the InnovationWell Autumn Program on Knowledge-based Innovation in Life Science Product Development:
http://barryhardy.blogs.com/theferryman/files/InnovationWell-ProgramAutumn05.PDF

And the equivalent eCheminfo brochure on Drug Discovery:
http://barryhardy.blogs.com/theferryman/files/eCheminfo-ProgramAutumn05.pdf

Note: The poster sessions will be run as electronic poster sessions using tabletop spaces, a wireless network and Internet facilities at the meetings, in addition to virtual access through the website, i.e., the posters will be electronic but the access can be face-to-face or virtual. You can participate in person and virtually in the poster sessions.  We can supply nourishment and refreshments locally; remote participants may have to order out! [We also expect, subject to on-site testing, to have live conference call capabilities for remote participating members to join local discussions.]  Anyone interested in presenting such an "electronic poster" should directly contact us via email at innovationwell at douglasconnect.com

Look forward to seeing you in Philadelphia or Basel!

Barry Hardy
Community of Practice Manager
Douglas Connect
http://douglasconnect.com/
+41 61 851 0170 (office)

InnovationWell & eCheminfo InterAction Meetings
Philadelphia, US, 11-12 October 2005 and Basel, Switzerland, 9-10 November
List of Sessions with Speakers & Schedule (InterAction Autumn Meetings)
http://innovationwell.net/ and http://echeminfo.com/

Registration to attend the meetings or to access virtually is available through the websites or through contacting Nicki Douglas [nicki.douglas at douglasconnect.com]

InnovationWell eCheminfo meeting workshop conference management executive drug safety KM Life Sciences Pharma Drug Discovery Drug Development Healthcare Innovation Informatics cheminformatics Knowledge Management events

…PROGRAM LISTING CONTINUING IN FULL POSTING…..

Making real molecules in virtual space

Gyorgy Pirok, Chief Technology Officer at ChemAxon, will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

Making real molecules in virtual space

Good quality virtual enumeration of combinatorial libraries requires the manual intervention of an experienced chemist (selecting appropriate reactants, assignment of the corresponding reaction sites, removing unlikely products) slowing down the entire enumeration process. Encoding the valuable knowledge of preparative organic chemists into the reaction schemes decreases the human factor in the library generation phase and opens new possibilities for researchers.

ChemAxon builds a reusable "smart" reaction library consisting of the most important synthetic reactions. These reaction definitions contain a generic transformation scheme and additional chemo-, regio- and stereoselectivity rules. The virtual synthesis application based on this technology is not only able to enumerate entire combichem libraries in a single pass, but also to build a diverse molecular space of synthetically feasible virtual compounds from available chemicals.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/
eCombiChemLeads Blog: http://barryhardy.blogs.com/ecombichemleads/

Discovery and Development of a Library of Novel (Pyrrolidino)diketopiperazines

Kevin Short, Johnson & Johnson will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

Discovery and Development of a Library of Novel (Pyrrolidino)diketopiperazines

Over the last 10 years, there has been great interest in the development of solid-phase synthetic approaches to small molecules, particularly those that embrace polyfunctional heterocyclic targets. As part of Ontogen's Combinatorial Chemistry program, we had an interest in developing synthetic strategies and chemistries applicable to combinatorial libraries of multisubstituted heterocycles. Following our early successes in the area of multisubstituted imidazoles, we applied the highly powerful Ugi reaction to the synthesis of hydantoin imides, tetrazoles and lactams. In addition, we reported on an Ugi-based library of diketopiperazines.

This seminar will describe the discovery of a novel bicyclic chemotype, prepared via a facile 2-step procedure, thus:

• an azomethine ylide-olefin [3+2] cycloaddition, followed by;
• a lactam forming reaction.

The procedure was adapted for use in an on-resin format, and a cyclative cleavage procedure utilizing the 2nd step furnished products in high purity. This presentation will detail the extensive optimization of the individual steps, both in solution and on-resin, followed by a ‘screening' of reagent inputs. Solid phase ‘rehearsal' of the library was carried out in ‘Test Plates', using the OntoBLOCK (TM) system. Extensive use of LC-MS and 1 H NMR analyses ensured a high information content for the rehearsal Test Plates, and ultimately a high confidence level for the ultimate production library's overall quality. The goal was to prepare a moderately large library of compounds.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/
eCombiChemLeads Blog: http://barryhardy.blogs.com/ecombichemleads/

Combinatorial Screening of Polymeric Coating Formulations

Jaime Grunlan, Senior Research Engineer, Avery Research Centre, will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

Combinatorial Screening of Polymeric Coating Formulations

A combinatorial factory for the preparation and screening of polymeric coatings is outlined here. The coating formulations are prepared and coated using a novel combinatorial coating technique to obtain combinatorial libraries of varying composition and thickness. The thickness of each film in a combinatorial array is rapidly determined via visible-light absorbance of optical dyes in conjunction with the Beer-Lambert relationship. These combinatorial libraries are then tested and screened using a variety of custom-made high-throughput methods. Combinatorial screening of oxygen and moisture transmission rate, along with pressure-sensitive adhesive properties, is presented. OTR and MVTR are determined using spectrometric techniques. For adhesion, a spherical probe adhesive tester is able to generate parameters linked to tack, peel, and shear in one measurement. In addition to describing the testing methodology, benefits and shortcomings of these techniques will be highlighted.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/
ECombiChemLeads Blog: http://barryhardy.blogs.com/ecombichemleads/

Utilizing SynPhase Scavenger Lantern Technology for the Synthesis of Small Molecule Combinatorial Libraries via solution-phase methodologies

Nicholas Ede, Head of the Discovery Products business unit of Mimotopes, will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

Utilizing SynPhase (TM) Scavenger Lantern Technology for the Synthesis of Small Molecule Combinatorial Libraries via solution-phase methodologies

Scavenging of unwanted reagents/reactants from solution phase reaction mixtures has emerged as an important alternative to contemporary purification of reaction mixtures in combinatorial chemistry. This allows for the parallel synthesis of large number of compounds in solution phase rapidly.

Mimotopes have designed and prepared several high loading Lanterns for use in scavenging applications. Combining the handling advantages with excellent scavenging capabilities, these new scavenger Lanterns are ideally suited for solution phase synthesis, particularly in a high throughput array format. This presentation will highlight a number of examples where scavenger Lanterns are used to make interesting drug-like compounds from, for example, Maybridge Reactive Intermediates such as 3,5-dimethylisoxazole-4-sulfonyl chloride. In addition, a simple and convenient solid phase synthesis of disubstituted guanidines which utilises the TMI-isocyanate SynPhase scavenger lantern 1 as a starting point will be presented (see Scheme below).

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/
eCombiChemLeads Blog: http://barryhardy.blogs.com/ecombichemleads/

New Linkers and Polymer-supported Reagents for Organic Synthesis

Dr. A. Ganesan, School of Chemistry, University of Southampton, UK will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

New Linkers and Polymer-supported Reagents for Organic Synthesis

The implementation of parallel chemistry demands new reagents for synthesis that are convenient and practical for high-throughput usage. At the same time, such tools must be robust and inexpensive. In this presentation, I will highlight two recent examples from our group. The first is a tetrafluoroarylsulfonate linker for solid-phase synthesis. It behaves as a ‘triflate' equivalent, and is suitable for both ‘traceless' cleavage as well as cleavage by Pd(0) catalyzed C-C bond forming reactions. The second application, for solution-phase synthesis, features cyclooctadiene immobilized on polystyrene at a high loading. This reagent functions as an electrophilic scavenger, and is readily converted to a polymer-supported version of the hydroborating reagent 9-BBN.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/
eCombiChemLeads – Blog on CombiChem News: http://barryhardy.blogs.com/ecombichemleads/

Drug Discovery by systematically scanning molecular space

Bernd Becker, Senior Research Scientist at Alchemia, will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

Drug Discovery by systematically scanning molecular space

Molecular recognition between a ligand and its receptor, is generally dictated by the correct three-dimensional presentation of the ‘essential' functionalities of the ligand to the receptor binding site. Peptidomimetic drug discovery involves mimicking those functionalities and their bioactive presentation. Current libraries are often limited in their ability to truly scan molecular space in search for the correct three-dimensional presentation, due to restrictions imposed by the scaffolds used. Carbohydrates present a family of naturally occurring scaffolds with easily manipulated hydroxy functionalities in a variety of orientations. By carefully selecting a series of orthogonally protected scaffolds these can be decorated with a variety of substituents in different ring-positions and orientations (axial/equatorial) to find the optimal presentation required for recognition.

This approach was applied to the design and synthesis of a library targeting a group of G-protein coupled receptors with a common recognition motive, including somatostatin and melanocortin receptors. The resulting library contained a large number of compounds that were highly active and selective for different receptors within the group.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/
eCombiChem Leads: http://barryhardy.blogs.com/ecombichemleads/

Application of microchannel flowreactors for lead optimization and library development

Ferenc Darvas, Ph.D., President and Chairman, ComGenex, Inc. will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

Application of microchannel flowreactors for lead optimization and library development

Combinatorial chemistry is a target/oriented, adaptive science that is now facing the challenge of fast developing fields such as micro and nanotechnologies. The drive towards miniaturization has several advantages, namely speed, increased reaction sensitivity and control and cost effectiveness.

An important development has been the utilization of microfabricated devices such as microchannel flow reactors for synthesis of general and focused libraries as well as for lead optimization. These micro devices can be defined as a series of minute interconnecting channel reactors in which chemical reactions are performed in a continuous flow. Continuous methods are widely used in chemical synthesis due to their lower operating costs and high efficiency, their main drawbacks being size, high set up costs and lack of flexibility. The development of continuous micro channel flowreactors has the potential to overcome these disadvantages due to their higher yields, and reaction selectivity and control, leading to an enhancement of both productivity and performance of combinatorial library synthesis, together with other unusual chemical and operation opportunities.

Microchannel flowreactors can perform standard homogenous, or heterogeneous, gas/solid/liquid phase reactions, which represent an efficient method for parallel synthesis of combinatorial libraries. A substantial increase of the reaction rate relative to the batch liquid phase reaction is generally achieved, thus allowing a faster synthesis of more and often highly purified compounds.

These microchannel flowreactors are safe and convenient to use in any laboratory and they are compatible with widely available robotic equipment. After a number of optimization rounds, the device can be used for any chemical synthesis under the desired conditions.

In this presentation an overview will be given on this rapidly developing field with specific examples as well as future trends described.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/

Target Class Library Design, Development and Production in Drug Discovery at Bristol-Myers Squibb

Christopher Cooper, Associate Director of New Leads Chemistry at Bristol-Myers Squibb, will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

Target Class Library Design, Development and Production: Recent Applications of the IRORI NanoKan™ Combinatorial Chemistry System

The dynamic environment of exploratory and early phase drug discovery research across the pharmaceutical industry has necessitated re-evaluations of the established paradigms at the Bristol-Myers Squibb Pharmaceutical Research Institute. Efforts to capitalize on concurrent advances in genomics, high capacity combinatorial chemistry, and high-throughput screening have resulted in new strategic approaches to drug discovery. In the areas of parallel synthesis and combinatorial chemistry, New Leads Chemistry has developed a fully integrated suite of technologies to address the current and anticipated needs for the Institute. An overview of gene family target class library design, the establishment of target class knowledge databases, and the resulting development and production of target class-biased combinatorial libraries will be presented including recent successful applications of the state-of-the-art IRORI NanoKan™ Combinatorial Chemistry System.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/