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MDL & Scitec, March 11, 1996


Information Management/Robotics Systems Accelerate Drug Research

SAN LEANDRO, California March 11, 1996 MDL Information Systems, Inc., (Nasdaq National Market System: MDLI) and Scitec Laboratory Automation, S.A., Lausanne, Switzerland, have agreed to integrate technologies that support high throughput screening (HTS) of potential drug compounds. HTS, an automation process that speeds lab research, is rapidly being adopted by companies in the pharmaceutical, agrochemical, and biotechnology industries. MDL, the leading supplier of chemical information management systems, recently announced MDL SCREEN, a client/server system that manages the vast amounts of data associated with HTS. Scitec is a major producer of robotics solutions for laboratory automation.

According to Thomas D. Jones, MDL s president and chief operating officer, Researchers can realize major productivity gains through high throughput screening. But to achieve those benefits, they need solutions that successfully integrate the core technologies of data management and robotics. Scitec is a world leader in software for robotics systems development and management. By integrating MDL SCREEN with Scitec products, we are helping our mutual customers get high throughput screening off the ground faster and with less cost. And we re providing a framework for reliable and efficient operation. Together, MDL and Scitec will speed the successful implementation of HTS throughout the industry.

Jean-Louis Rufener, president of Scitec Laboratory Automation, said, High throughput screening creates enormous demands for strong, efficient information management. Now we can build upon our broad background in multi-vendor and networked robotics systems to address those needs through integration with MDL SCREEN. Our agreement with MDL helps us deliver a more comprehensive solution to our customers.

About the Companies

Scitec is an international company and a pioneer in the development and use of complex robotics systems for the analytical laboratory. Its CLARA software for robotics system development and management has been adopted by the largest pharmaceutical companies in the world. Scitec s capabilities in both hardware and software integration and development enable organizations to implement robotics solutions meeting the highest requirements for reliability, productivity and flexibility.

Established in 1978, MDL Information Systems, Inc. is the leading commercial supplier of chemical information management software, chemical information databases, and related services to the pharmaceutical, agrochemical, and chemical industries. The company's software and database products enable its customers to discover and develop new products more rapidly by allowing scientists to access and use scientific information more effectively. MDL has offices worldwide with headquarters in San Leandro, California.

The statements which are not historical facts contained in this release are forward-looking statements that involve riss and uncertainties, including, but not limited to, product demand and market acceptance risks, the effect of economic conditions, the impact of competitive products and pricing, product development, commercialization and technological difficulties, and other risks detailed in the Company s Securities and Exchange Commission filings.

MDL and MDL SCREEN are registered trademarks of MDL Information Systems, Inc. All other products are trademarks or registered trademarks of their respective holders.

Sketch & Fetch by Tripos

Tripos has created a chemical searching application based on Web technology and we would like you to try it. We believe that Web technologies offer an effective means to provide access to design tools on a range of hardware platforms such as Mac's and PC's. This application is the first step in delivering the molecular design and analysis expertise of Sybyl and UNITY at the desktop.

To separate reality from hype, we built an application called "Sketch and Fetch" which is now available on the web with access from multiple sites including the Tripos homepage (http://www.webcom.com/~tripos2) and the Silicon Graphics ChemBio page (http://www.sgi.com/ChemBio under What's New).

"Sketch & Fetch" is a Web-based application built with Java applets. Sketch & Fetch provides a simple WebSketcher(tm) to (1) enter a 2D query, (2) choose a UNITY database and (3) initiate a search. Structures matching the query are returned and displayed in a 3D viewer in the page (also a Java applet). The structures can be rotated and manipulated.

Subsets from three commercial databases are on-line for searching -- Chapman & Hall, Current Drugs and Derwent's WDI. Hyperlinks provide information about each of the databases. The complete databases (and others) are available in UNITY format from Tripos.

"Sketch and Fetch" requires Java and was developed using Netscape Navigator(tm) 2.0. Navigator 2.0 is available for most platforms and can be downloaded from their web page (http://www.netscape.com). Other Java-capable browsers may also work. A user without a Java-capable Browser is given a description of the applet's function but cannot use the sketcher.

I encourage you to give this application a try and let us know what you think. Participants who register are eligible for a prize drawing. Comments and inquiries can be made directly from the web page or can be sent directly to the Database Product Manager, Sheila Ash (sash@tripos.com).

This application is the first step in delivering the drug design expertise of Sybyl and UNITY at the desktop using web technology. Tripos would like to thank Silicon Graphics for their assistance and for their cooperation in providing access to their web servers, making this application available worldwide; Derwent, Chapman and Hall and Current Drugs for allowing us to make a subset of their data available on-line.

Dean Goddette, Ph.D.
Senior Product Manager
1699 S. Hanley Road
St. Louis, MO 63144
Tel: (314) 647-1099 X3386
Fax: (314) 647-9241

Sketch & Fetch:http://www.sgi.com/ChemBio (under What's New)
Tripos Home Page:http://www.webcom.com/~tripos2
Sheila Ash e-mail:sash@tripos.com

MDL & Tripos 12 February 1996


ST. LOUIS, Missouri February 12, 1996 MDL Information Systems, Inc. (Nasdaq National Market System: MDLI), a leading supplier of chemical information management systems, and Tripos, Inc. (Nasdaq: TRPS), a leading supplier of molecular discovery, design, and analysis technologies, today announced a collaboration to provide integrated software solutions. These solutions will incorporate simulation, analysis, and database management capabilities for customers in the pharmaceutical, agrochemical, and chemical industries. The two companies will accomplish this by separately offering products that in combination provide comprehensive, integrated solutions addressing customer needs in areas such as combinatorial chemistry and molecular design and analysis. Each company will continue to develop technologies independently while working on integration of key products.

The goal of this collaboration is to provide more comprehensive solutions that help customers accelerate the compound discovery process and enhance research productivity. The two firms will collaborate initially in combinatorial chemistry informatics, a new technology that is revolutionizing compound research methods. Tripos was the first company to deliver molecular diversity technology tools for combinatorial library design, storage, and analysis and has expertise in pharmacological activity prediction. MDL was the first company to deliver combinatorial chemistry data management tools and has additional expertise in library management, workflow support, and databases of reactions and reagent information.

The other initial area of major collaboration will be in combined solutions for molecular design and analysis. Researchers will benefit from transparent access to MDL s databases and ISIS, an open, client/server scientific information management system, from Tripos products including SYBYL (advanced molecular design and analysis), Alchemy (desktop molecular design) and Unity (integrated 3D database system for bio-active molecular discovery).

Tripos will rely on ISIS as the information pipeline for its design solution. Tripos will continue to aggressively develop and improve Unity for 3D searching and analysis. Tripos announced that it intends to cease further development of Unison and will work with MDL to allow Unison customers to convert their current systems to integrated solutions based on ISIS.

Steven Goldby, MDL's chairman and CEO, said, MDL and Tripos each have achieved leadership in complementary technologies, and we are now combining these strengths to better serve our customers. The beauty of this arrangement is that each company can concentrate on the things it does best for new compound discovery. MDL's customers will benefit in many ways. ISIS users will have easier access to Tripos integrated design and analysis applications. We look forward to a long relationship in which we continue to exploit opportunities for innovative shared solutions.

John McAlister, president and CEO of Tripos said, "Tripos' collaboration with MDL will rpovide our customers with the unique opportunity to combine their data management facilities with data analysis, modeling, and experimental design in a seamless fashion. As Tripos focuses more of its efforts on new compound discovery and combinatorial library design, our customers will benefit from rapid product innovation and deployment. We are confident that this alliance will significantly advance the use and application of high technology and computational methods in pharmaceutical, agrochemical, and chemical research."

About the Companies

Tripos, Inc., with headquarters in St. Louis, Missouri and offices worldwide, is a leader in the creation, development, and delivery of chemical libraries, discovery software and related services to facilitate the discovery of new therapeutic and bioactive compounds in the pharmaceutical, biotechnology, chemical, and agrochemical industries. The customer base includes the world s largest scientific research organizations.

Established in 1978, MDL Information Systems, Inc. is a leading commercial supplier of chemical information management software, chemical information databases, and related services to the pharmaceutical, agrochemical, and chemical industries. The company's software and database products enable its customers to discover and develop new products more rapidly by allowing scientists to access and use scientific information more effectively. MDL has offices worldwide with headquarters in San Leandro, California.

MDL is a registered trademark of MDL Information Systems, Inc. ISIS is a trademark of MDL Information Systems, Inc. Unity, SYBYL, and Alchemy are registered trademarks of Tripos, Inc. All other products are trademarks or registered trademarks of their respective holders.

The statements which are not historical facts contained in this release are forward-looking statements that involve risks and uncertainties, including, but not limited to, product demand and market acceptance risks, the effect of economic conditions, the impact of competitive products and pricing, product development, commercialization and technological difficulties, and other risks detailed in both Companies Securities and Exchange Commission filings.

Collection for HTS 6 March 1996

Hope that the following information could be interesting for you.

NEW O.S.T. Collection for High-Throughput Screening.

Your colleagues for Ukraine are very glad to represent new collection of small molecules for high-throughput screening. The collection is gathered from more than a hundred Ukrainian chemists representing more than twenty scientific institutions. Currently we have about 4,500 compounds in our database and this figure grows constantly. The database has friendly ISIS/Base format.

The O.S.T. collection is easily available for preview prior to purchase.

If you are interested you are welcome to contact us for more details on the O.S.T. Collection.

With best regards,
Maxim A. Kharchenko
OAK Samples Trading, Ltd.
5 Sapernoye pole St.
252042 Kyiv
Tel: +380 44 269-3467
Fax: +380 44 269-3467 (local night hours)

Collection of Organic Substances 27 February 1996

ChemStar, Ltd., offers research co-operation in the field of screening of organic substances for discovery of new materials for pharmacology, agriculture and other application.

ChemStar, Ltd., offer samples of organic compounds for screening in the range of 20 -1000 mg. Furthermore, ChemStar, Ltd., offers an efficient custom synthesis capabilities in Russia.

ChemStar, Ltd., was founded by independent private Moscow constitutors. We represent chemists working in the laboratories of the Commonwealth of Independent States (CIS).

ChemStar, Ltd., develops and maintains a fast growing library and database of organic compounds. The whole list of currently available substances exceeds 180 000. The compounds in our library and database were collected from several hundred unique sources in Russia and other States of the CIS. Thousand more new structures are being added to ChemStar 's library each month. We use ChemBase and ISISbase to support our database.

If you are interested in particular types, class or groups of compounds, we can carry out selection from our full library according to your requirements.

Diverse and complex organic substances are available both on exclusive and non-exclusive bases.

You can receive samples selected for your screening programs in a short time (2 month approximately).

Purity of samples is no less than 90-95%. We provide 100% NMR control of the samples supplied. 1H NMR spectra are recorded at 300 or 400 MHz spectrometers. As needed we can carry out 13C NMR and GC/MS control.

You can specify the type of packaging that suits your specific needs. We use plastic vials, however, we can pack in your vessels, too.

Looking forward to continue co-operation,

Sincerely yours,

Dr. Svetlana Vorob'eva ChemStar, Ltd., President

For further information, please contact:
ChemStar, Ltd.,
P.O. Box 191, Moscow, 103536, Russia,
Tel/Fax: + 7 095 5369411,
E-mail: sv@svetlv.msk.ru

News Release - 29th January 1996

New Release of Accord for Microsoft Access Supports Reactions

Synopsys Scientific Systems Ltd. today announced the release of Version 1.1 of Accord for Access, it's best-selling desktop chemical/relational database system. This new, improved version provides full support for the storage, searching and display of reactions, plus a host of other exciting enhancements. With Accord for Access, databases containing tens of thousands of chemical structures or reactions can be typically searched by substructure in seconds on a standard desktop PC. State-of-the-art indexing techniques allow Accord's chemical search engine, which is fully integrated into Access, to process queries in record time. What's more, atom-to-atom correspondences can be used t define the reaction transformation of interest. This means that users can indicate precisely the information they want to be returned from reaction substructure searches.

Accord for Access provides full support for reaction information. Reactions and associated data can be imported and exported to and from relational tables in a number of standard formats, including RD and SMD. Hierarchical data can be mapped to a series of relational tables in Access, making import of existing databases quick and easy. Users can perform exact, substructure or similarity searches, then transfer data sets of interest to Accord for Excel, for further spreadsheet analysis - all at the push of a button. Similarly, reactions can be transferred via the clipboard or via files in a variety of formats, including MDL Rxnfile and ISIS Sketchfile, for editing purposes or further processing as required.

In addition to support for reactions, Accord for Access 1.1 provides users with a host of other new, exciting capabilities. Users now have the option of creating native Access Chemistry Tables. This option means that distributing finished applications to end-users is quick and easy, as there is only one database file to ship. New query functions have been introduced to support Access Basic developers. The new version of the software also features performance gains, improved localised installation and a number of enhancements suggested by users.

Dr. Keith Harrington, US Sales & Marketing Manager at Synopsys, commented: "Version 1.1 of Accord for Access offers considerable additional benefits to users. With unified handling of molecules and reactions, full SQL support allowing both chemical and non-chemical data to be search in a single query, genuine multi-user access and fast response times, the product sets a new standard for desktop chemical database software."

Accord for Access is compatible with Microsoft Access 2.0 or higher and Microsoft Windows 3.1 or higher. Standard chemical editors, such as ChemDraw, ChemWindow and ISIS/Draw, can be used to enter and modify structures, reactions and queries. Accord for Access is fully compatible with Accord for Microsoft Excel, Accord Visual Objects and the Accord Software Development Kit.

Accord for Access - Availability & Pricing
Version 1.1 of Accord for Access is priced at 695 ($995 in the USA); a 40% discount is available to academics and students.

Background Information
Accord for Access is chemical, relational, multi-user and fast, making it the ideal tool for stand-alone and project-level chemical database applications alike. Because Accord enables Access to understand chemistry the way chemists d - using the language of structural diagrams - its intuitive and easy to use. Based on an open systems, component software architecture and utilising OLE 2.0 integration standards, Accord for Access provides a radical, new approach to meeting the chemical data handling needs of chemists and IT professionals. Synopsys Scientific Systems is a leading provider of computerised scientific information products and services to the Fine Chemical and Pharmaceutical Industry. Synopsys' flagship Accord software range is used worldwide by scientists to transform raw chemical data into useful information. Synopsys ha offices in Europe and the USA, with marketing partners in Japan and Korea. For further press information, please contact Dr. Glen Hopkinson or Dr. Keith Harrington at Synopsys.

For more info contact:
Tel: +44 (0)113 245 3339
Fax: +44 (0)113 243 8733


Dr Keith A Harrington
US Sales & Marketing Manager
Tel: +44 (0)113 245 3339
Fax: +44 (0)113 243 8733

Chemical Screening and Analysis Package

CSAP (Chemical Screening and Analysis Package) - HTS Data Management System CSAP is a Microsoft Access database application designed for managing chemicals in drug discovery programs. CSAP organizes and analyzes chemical collections throughout the screening process providing researchers with a coherent decision making system for a notoriously chaotic information bottleneck.

CSAP can run as a stand alone database on a single PC for smaller operations or it can be connected directly to a powerful client server application like Oracle for almost unlimited capacity. Microsoft provides drivers for seamless connections to numerous industry standart databases with no changes to the Access user environment.

CSAP has built in graphics that facilitate plate analysis and approval. The status of individual wells on a plate is indicated by a color code that allows the analyst to spot problems and find actives instantly. CASP provides the following capabilities:

CSAP is a completely open architecture and Access is relatively easy to use therfore users with minimum skill can create custom forms, reports and queries. This is an extremely important feature that anyone forced to find a programmer to create simple reports can attest to. If extensive modifications are required a competent database programmer can modify all the components of CSAP since there is no inaccessible source code in operation.

The person to get in contact at MLR Automation is:

Chip Allee
204 Littlefield Avenue
South San Francisco
CA 94080


Bio Online, a very popular web site dedicated to the biopharmaceutical industry (http://www.bio.com), has added an extensive, growing and convenient collection of life sciences-related software for sale in the Bio Online Marketplace Store. Software is available from a wide range of disciplines: biology, molecular biology, genetics, medicine, environmental science, chemistry (organic, theoretical, analytical), molecular modeling and design (computational and QSAR), productivity (structure drawing, graphing, databases, research organizers, planners), and statistics, as well as some relevant business modeling and planning software. Prices range from low cost educational software up to full featured research software for PC, MAC and UNIX. Visa/MasterCard orders can be accepted directly online using secure server technology (Netscape) or by conventional methods such as fax, phone or e-mail.

Bio Online, boasting over 200,000 page accesses per week, features extensive industry information sources (several are unique to the site, as well as a comprehensive Career Center). There are up-to-date news and events sections, corporate biotech directories, press releases, and product information, as well as hot-links to other Internet research, education and government sites. It is produced by Vitadata Corporation, with sponsorship by KPMG Peat Marwick, Heller Ehrman White & McAuliffe and Corning Pharmaceutical Services. Technical software is made available through a collaborative effort with BioSoftware Marketing.

contact: Vitadata - John Turkel, ph: 510-548-1171
BioSoftware Marketing - Stefan Unger, ph: 415-858-0522

Stefan Unger, Ph.D.
BioSoftware Marketing
4151 Middlefield Rd., Ste 109
Palo Alto, CA 94303-4743

BioSoftware Marketing specializes in a full range of marketing services (market studies to collateral design and production) for start-up and small technical software companies, especially biopharm related. E-mail your full mailing address to receive a full-color brochure describing these services. We also offer consulting on computer aided drug design and biological/chemical databases.

ActivityBase (now in version 2.0)

ActivityBase (now in version 2.0) is produced by:
ID Business Solutions
in London
Tel: +44 (0) 171 828 1999

It is designed for use by biologists in activity testing programs. It allows for GLP, integrates with Microsoft Office products and lets you define assays as protocols. You can calculate results, capture data from experiments, initiate and track test requests and organize protocols and users. [This is what it says on the literature - here's your chance to organize your biologists!]. Chemical structures are held as SMILES codes. ActivityBase offers biological form registration and querying the forms and producing reports. It can connect to any ODBC compliant database and has direct links to ORACLE and SQL Server. IDBS also offers a full range of COMPLIMENTARY support, training and consulting services. Perhaps they do offer their services for free - or perhaps their software is better than their spelling?

Course in Molecular Diversity January 16, 1996



Starting in January 1996, chemistry students at the University of Louisville (Kentucky) will be offered a full semester course in the hot area of Combinatorial Chemistry and Molecular Diversity. Professor Arno F. Spatola of Louisville, an organic/peptide chemist, cites the increasing interest within the pharmaceutical and biotechnology industries for preparing and testing "molecules by the billions" as a motivator for this new venture. Among the unique features of this course are guest appearances by eight of the top pioneers in combinatorial chemistry and related subjects including Dr. Mario Geysen, Senior Research Scientist at Glaxo Wellcome, Dr. Richard Houghten, President of San Diego's Torrey Pines Institute for Molecular Studies, Dr. Sheila Hobbs-DeWitt, Vice President of Diversomer Technology, a Parke-Davis subsidiary, Dr. Michal Lebl, Selectide (Division of Hoechst) Dr. Jeff Jacobs, Affymax, Dr. Phil Andrews, University of Michigan, and Dr. Baldomero Olivera, Professor of Biology at the University of Utah. Financial support for travel, audio-visual enhancements, computer molecular modelling, and other costs are being provided by grants from pharmaceutical companies including Boehringer-Ingelheim Pharmaceuticals, Lilly, Parke-Davis, and Pfizer.

ADDITIONAL BACKGROUND: In 1963, R. Bruce Merrifield (Nobel Prize in chemistry, 1984) introduced the concept of solid phase peptide synthesis (SPPS) whereby amino acid chains as short as two (dipeptides) as well as longer (protein) chains could be made assembly-line fashion using automated peptide synthesizers. In the 1980s, Australian Mario Geysen showed SPPS could be the basis of multiple peptide synthesis, thus paving the way for later pioneers such as Furka of Hungary and Lam and Houghten of the U.S., to prepare peptides as mixtures. These mixtures can be tested for a particular biological activity, and, if found active, the identity of the active component(s) revealed by a variety of clever "deconvolution" strategies.

Intriguingly, the synthesis of mixtures for more rapidly discovering active principles is also found in nature. Biologist Baldomero Olivera of Utah has found that deadly cone snails produce hundreds of variants of a similar molecule in their venom, and many of these molecules have a rich diversity of biological actions.

University of Louisville
Chemistry 557
Bioorganic Phenomena
Spring 1996


Chemistry Viewer

News Release - 8th January 1996, For Immediate Release

Synopsys Makes Its Accord Chemistry Viewer Available Free On The Internet

Synopsys Scientific Systems Ltd., a leading provider of chemical information software and database solutions, today announced the availability of its Accord Chemistry Viewer free on the Internet World Wide Web for personal, academic and registered corporate use.

The Accord Chemistry Viewer can be installed as a helper application within Web Browsers, such as NetScape or Mosaic, to retrieve and depict chemical structure and reactions from Web servers stored in a host of chemical formats, including SMILES strings, ChemDraw files, MDL Molfiles and Rxnfiles. The Accord Chemistry Viewer also makes it possible to visualise chemistry stored as MIME attachments in Internet Mail Messages.

Because Accord enables Web Browsers to understand chemistry the way chemists do - using the language of structural diagrams - it's intuitive and very easy to use. The Accord Chemistry Viewer provides a new, flexible approach to visualising chemical data on the Internet. In addition, publication-quality chemical diagrams produced by the Accord Chemistry Viewer can be transferred vi the clipboard to other desktop applications quickly and easily for inclusion in internal reports, etc.

Applications of the full Accord Chemistry Viewer extend beyond the Internet. Ia Buchan, Project Manager at Synopsys, commented: "Accord's open, component architecture means that the Chemistry Viewer is an indispensable tool for visualising chemistry on the desktop. This technology is an important component of commercial Accord-based solutions based on OLE, such as Accord for Microsoft Access and the Accord VBX. By making the basic Accord Chemistry Viewer free on the Internet, we hope scientists and information professionals will be better able to communicate good chemistry and, at the same time, tune into the benefit of the Accord component software approach."


The Accord Chemistry Viewer is compatible with Microsoft Windows 3.1 or higher. A Macintosh version is scheduled for release in March 1996.


Version 1.0 of the Accord Chemistry Viewer is available free of charge and can soon be downloaded from Synopsys' Home Page at http://www.synopsys.co.uk/. Instructions for installation and use are provided. A stand-alone installation disk and more information on the Accord chemical software suite (Accord for Microsoft Access, Accord for Microsoft Excel, Accord Visual Objects and the Accord Software Development Kit) can be obtained by sending e-mail to sales@synopsys.co.uk

About Synopsys...

Synopsys Scientific Systems is a leading provider of computerised scientific information products and services to the Fine Chemical and Pharmaceutical Industry. Synopsys' flagship Accord software range is used worldwide by scientists to transform raw chemical data into useful information. Synopsys has offices in Europe and the USA, with marketing partners in Japan and Korea.

For further press information, please contact Dr. Glen Hopkinson or Dr. Paul Hoyle at Synopsys.
Tel: +44 (0)113 245 3339
Fax: +44 (0)113 243 8733
E-mail: sales@synopsys.co.uk

3DPharmaceuticals Patent


'Will Have Special and Immediate Relevance to the Field of Combinatorial Chemistry'

Exton, PA -- October 31, 1995 -- 3-Dimensional Pharmaceuticals, Inc. (3DP) today announced a broad new patent (U.S. Patent #5,463,564) that covers the automatic generation of new drug leads through computer-controlled, iterative robotic synthesis and analysis of chemical libraries -- a technology the company has named DirectedDiversity.

'We believe that 3DP's DirectedDiversity technology has the potential to have a profound effect on the future of drug discovery' said F. Raymond Salemme, Ph.D., president and chief executive officer. 'It controls the process of discovering chemical compounds in much the way that a computer's operating system controls the computer. It is capable of producing important new pharmaceuticals more efficiently and at far less cost than has previously been possible. This patent will have special and immediate relevance to the field of combinatorial chemistry'. The 3DP patent application was granted 'Special Status', meriting accelerated review by the U.S. Patent and Trademark Office.

'Traditional Drug Discovery Methods Have Not Kept Pace'

The recent surge of human gene discoveries has produced a dramatic increase in new molecular targets known to play a significant role in causing disease. Traditional drug discovery methods, dependent on synthesis and testing of compounds one by one, have proved incapable of keeping up with the demand for new compounds to test against all the newly discovered targets. 'The limitations of conventional pharmaceutical research are a fundamental reason for the high cost and slow pace of drug discovery', noted Dr. Salemme. 'We believe DirectedDiversity will enable us to bring new therapies to patients who need them more rapidly than ever before'.

'Harnessing the Potential of Combinatorial Chemistry'

'In just the last couple of years, the pharmaceutical industry has adopted combinatorial chemistry as a way to multiply the number of new drug leads', Dr. Salemme said. Combinatorial chemistry can produce hundreds of thousands, or even millions, of molecules by chemically combining and recombining basic molecular building blocks in different configurations. The challenge is how to identify, out of these huge numbers of molecules, those which have the potential to become important new pharmaceuticals.

'Unlike other combinatorial approaches which tend to generate libraries of compounds at random, DirectedDiversity is an iterative optimization process that explores combinatorial space through successive rounds of selection, synthesis and testing', said Dr. Salemme. 'Our process captures and uses vast amounts of information to develop libraries of novel, small molecule drugs by selectively combining a particular set of chemical building blocks. DirectedDiversity is an operating system that is capable of harnessing the potential of combinatorial chemistry'.

DirectedDiversity Retains and Learns from the Information It Generates

DirectedDiversity is a computer-aided, iterative process for generating chemical compounds with a prescribed set of physical, chemical and/or biological properties. During each iteration, a chemical library is robotically generated, and the structure and activity of individual molecules in the library are analyzed to determine how closely they match the desired set of properties. A database records all observed structural data, measured activity and computed properties for each compound analyzed in the form of structure-activity models.

Using the information 'learned' from these structure-activity models, the DirectedDiversity process begins the next iteration by formulating new instructions to control synthesis of the next generation of compounds. In each succeeding iteration, existing structure-activity models are refined and new models are constructed -- automatically applying the information gained in previous iterations. This process continues until the desired new drug leads have been identified.

The DirectedDiversity technology was developed exclusively by a team of 3DP scientists. The inventors named in the patent are Dimitris K. Agrafiotis, Ph.D.; Roger F. Bone, Ph.D.; F. Raymond Salemme, Ph.D.; and Richard M. Soll, Ph.D.

The patent covers the use of semi-automated and automated feedback control for generating combinatorial libraries and refining their properties -- and extends to applications where suitable properties can be measured, including drugs, herbicides, paints, scents, solvents, advanced materials, etc. 3DP intends to license DirectedDiversity technology to a select number of major pharmaceutical companies -- and 3DP scientists are already using it to discover and refine drugs active against a wide range of targets such as receptors and enzymes known to be implicated in cardiovascular disease, autoimmune disease and cancer.

3-Dimensional Pharmaceuticals, Inc. was founded in 1993 to integrate advanced technologies in structure-based drug design, combinatorial chemistry and chemi-informatics for the cost-effective discovery of orally active pharmaceuticals.

DirectedDiversity United States Patent No. 5,463,564


A series of steps incorporating the following operations:
1. Robotic library synthesis
2. Robotic analysis
a. Assays for properties
b. Structure for compositional analysis
3. Computer identification of compounds with prescribed properties
4. Computer classification of active leads
5. Computer development of Structure-Activity Relationship (SAR) models
6. Computer selection, with or without operator input, of next compound set
a. Compounds predicted to match desired properties
b. Compounds to validate SAR models
c. Compounds to discriminate between SAR models
d. Compounds predicted to fit 3-dimensional receptor binding sites
7. Computer generation, with or without operator input, of chemical synthesis robot instructions
8. Iteration through steps 1-7

Issued October 31, 1995 to 3-Dimensional Pharmaceuticals, Inc.

Dimitris K. Agrafiotis, PhD
Principal Research Scientist
3-Dimensional Pharmaceuticals, Inc.
665 Stockton Drive, Suite 104
Exton, PA 19341
tel: (610) 458-6045
fax: (610) 458-8249
e-mail: dimitris@3dp.com

Diversomer Synthesizer

The "Diversomer 8-PIN Synthesizer" is currently being marketed by Chemglass for the parallel synthesis of 8 compounds by solution or solid phase chemistry. The reactor accomodates 100 mg of polystyrene resin. Below is a summary of the price list and contact information:

Diversomer 8-PIN Synthesizer = $395
(Glassware ordered separately)
PINS (pkg of 10) = $150
Reservoir Vials (Pkg of 10) = $15
Total cost for 8-PIN unit (with glassware) = $560

Contact Information:
Mike Kell
Director of Marketing
3861 North Mill Road
Vineland, NJ 08360
Phone: 800-843-1794
Fax: 800-922-4361

Although we have equipment at Parke-Davis to accomodate 800 mg of resin in each reactor, it is not currently available commercially.

However, Parke-Davis issued a press release on November 17, 1995 announcing that it is establishing DIVERSOMER Technologies Inc. (DTI) as a start-up company to commercialize the DIVERSOMER system for small molecule automated organic synthesis and combinatorial chemistry. Please call one of the individuals listed below if you would like additional information about DTI.

Sheila DeWitt, Ph.D.
Vice President
Technical Development
DIVERSOMER Technologies, Inc.
Phone: 313-996-7418
E-mail: dewitts@aa.wl.com

James Sherblom
Seaflower Associates
Phone: 617-466-9552

James Bristol, Ph.D.
Vice President Chemistry
Parke-Davis Pharmaceutical Research
Warner-Lambert Company
Phone: 313-996-7355