Computational Techniques in the Drug Design

Computational Techniques in the Drug Design Process

David Young
Cytoclonal Pharmaceutics Inc.

The purpose of this document is to outline the drug design process and specifically the role of computational modeling techniques. This is not meant to be a comprehensive review. It is meant to list the most important techniques currently in use.

The process of designing a new drug and bringing it to market is very complex. According to a 1997 government report, it takes 12 years and 350 million dollars for the average new drug to go from the research laboratory to patient use. Pieces of this process are often repeated to create successively better drugs for the same condition. In the case of antibiotics, drugs loose effectiveness as an immunity is built up, thus leading to a continuing "arms race". The major steps in the drug design process "from scratch" are.

1. FIND WHAT IS KNOWN

   Find out all that is known about the disease and existing or traditional remedies. It is also important to look at very similar afflictions and their known treatments.

2. DEVELOP AN ASSAY

   Develop an assay technique to test drug effectiveness. An ideal assay is one in which a compound can be added to tissue samples or micro-organism colonies and there will be a visible indication of an effective treatment. At worst, there must be a way to test the drug on a laboratory animal that is susceptible to the disease. If the only way to test the effectiveness of a trial compound is to inject an untested compound into a human subject then there is no way to proceed in finding a pharmaceutical treatment.

3. CONSIDER FINANCIAL ISSUES

   The next step is to make a financial decision about whether to proceed with the development process. The assay technique will determine the cost of testing compounds. If there are existing chemical treatments, it will be a refinement effort which saves the expense of finding lead compounds. All drugs must go through extensive testing so this is a fairly fixed cost. There may be governmental grants or tax incentives associated with certain diseases. The number of patients requiring treatment and merits of existing treatments will determine the long term profitability of producing a drug.
Steps 4 and 5 of this procedure are often performed simultaneously.

4. FIND LEAD COMPOUNDS

   Lead compounds are compounds that have some activity against a disease. These may be only marginally useful and may have severe side effects. However, the lead compounds provide a starting point for refinement of the chemical structures. Lead compounds may come from many sources, including
1. The isolation of active compounds from traditional remedies.
2. The testing of natural materials followed by an isolation effort.
3. Drugs effective against similar diseases.
4. Use of combinatorial chemistry techniques which produce large numbers of related chemical compounds. This allows testing a large number of compounds at once. When a mixture that is useful is found, a separation must be done to determine which of the related structures has some drug activity. This has been one of the most promising and rapidly growing techniques in recent years.
5. Searching chemical databases to find compounds similar to those found by the above means. This is the only part of the lead finding process that is considered to be a computational technique. There are many different measures of molecular similarity and ways of efficiently handling large databases, so this is not yet a trivial step.

5. ISOLATE THE MOLECULAR BASIS FOR THE DISEASE

   If it is known that a drug must bind to a particular spot on a particular protein or nucleotide then a drug can be tailor made to bind at that site. This is often modeled computationally using any of several different techniques. Traditionally, the primary way of determining what compounds would be tested computationally was provided by the researchers' understanding of molecular interactions. A second method is the brute force testing of large numbers of compounds from a database of available structures.

   More recently a set of techniques, called rational drug design techniques or De Novo techniques have been used. These techniques attempt to reproduce the researchers' understanding of how to choose likely compounds built into a software package that is capable of modeling a very large number of compounds in an automated way. Many different algorithms have been used for this type of testing, many of which were adapted from artificial intelligence applications. No clear standard has yet emerged in this area so it is impossible to say what is best the best technique at this time.

   These techniques have seen quite a bit of active development in recent years. Unfortunately, the complexity of biological systems makes it very difficult to determine the structures of large biomolecules. Ideally a x-ray chrystallography structure is desired, but biomolecules are very difficult to chrystalize. Another very useful technique, called "distance geometry" is to find some of the internuclear distances using NMR Nuclear Overhauser Effect experiments then find molecular geometries that have these distances. If only a protein sequence is known, there are many techniques for predicting how that protein will fold, but none has yet been shown to be 100% reliable. Even once a structure has been determined, identifying the site where a drug must bind is not a trivial task.

   The difficulty in find geometries makes it possible to bring first generation drugs to market by refinement of lead compounds without ever knowing the target site for the drug in the body. As such, these techniques are being used primarily for designing improved treatments for diseases that have already been characterized extensively.

6. REFINE DRUG ACTIVITY

   Once a number of lead compounds have been found, computational and laboratory techniques have been very successful in refining the molecular structures to give a greater drug activity and fewer side effects. This is done both in the laboratory and computationally by examining the molecular structures to determine which aspects are responsible for both the drug activity and the side effects.

   Synthetically, functional groups are removed in order to find out which must be present to give a useful drug and which are not necessary. The back bone of the structure is made more flexible or more rigid. A rigid back bone may hold the functional groups in the exact alignment necessary for the drug to bind. A flexible back bone may be necessary to allow the drug to get into the binding site. Adding bulky groups at other points on the molecule is often done in the hopes that these new groups may hinder the molecule from binding at unwanted sites which are responsible for the side effects.

   Computationally, the technique used is known as QSAR (Quantitative Structure Activity Relationships). It consists of computing every possible number that can describe a molecule then doing an enormous curve fit to find out which aspects of the molecule correlate well with the drug activity or side effect severity. This information can then be used to suggest new chemical modifications for synthesis and testing.

   Another important aspect of the molecular structure is its solubility. Whether the molecule is water soluble or readily soluble in fatty tissue will affect what part of the body it becomes concentrated in. The ability to get a drug to the correct part of the body is an important factor in its potency.

   Ideally there is a continual exchange of information between the researchers doing QSAR studies, synthesis and testing. These techniques are frequently used and often very successful since they do not rely on knowning the biological basis of the disease which can be very difficult to determine.

7. DRUG TESTING

   Once a drug has been shown to be effective by an initial assay technique, much more testing must be done before it can be given to human patients. Animal testing is the primary type of testing at this stage. The scientists doing the testing must be particularly observant of many little details since this is where unexpected side effects can be found. Another question to be answered is whether the drug will work well or poorly with other drugs. This is also where initial data necessary to determine correct dosages is obtained.

   Eventually, the compounds which are deemed suitable at this stage are sent on to clinical trials. In the clinical trials, additional side effects may be found and human dosages are determined. The typical testing process goes like this.

   1. Preclinical testing in animals and test tubes. This takes an average of 6.5 years. Only one compound in 1000 is sent on to clinical testing.
   2. Phase I clinical trials in a few human volunteers. This typically takes a year and a half. Seventy percent of the compounds are sent on to the next step. This is primarily a safety test.
   3. Phase II clinical trials in a few hundred patients. This takes two years and a third of the compounds are passed on to the next step. This is further safety testing and an initial examination of the ability of the drug to have the intended effect in humans.
   4. Phase III clinical trials in a few thousand patients. This step collects more data on safety, dosage, drug activity and side effects. About a quarter of the compounds pass this phase.
   5. An advisory panel of doctors reviews the data and makes recommendations to the FDA.
   6. FDA approval or rejection.
   7. The FDA continues to monitor drug performance long after approval has been given.

8. FORMULATION

   Before a drug can be produced, there must be a means to administer it. Ideally, a tasteless or bland tablet can be created. Alternatively, an oral liquid, intravenous injection or directly applied cream may be created.

   Tablets are created by adding other compounds to minimize stomach upset and control timed release of the drug. A tablet may also have a compound which is a matrix that helps it hold it's shape without crumbling into a powder.

   Oral liquids are often combined with strong flavors and alcohol to mask the taste of the drug and prevent throat irritation.

   A cream may have to be thickened or have a component that the skin will absorb readily.

9. PRODUCTION

   The large scale production of complex molecules can be very difficult. Compounds originally isolated from natural products may continue to be harvested. Often natural products are found in nature only in extremely small quantities necessitating a complex synthesis. One route that has been under development more recently is to have compounds produced by genetically engineered micro-organisms or plants.

   Drugs have a high value per gram. As such production techniques can be viable even though they are far more inefficient than those used by bulk chemical producers. Often all possible production techniques are researched even though only one will be put into practice. This is done so that there are no openings for competing corporations to get around a manufacturers patents by using a different technique.

   Manufacturing regulations have become much more stringent in recent years. It is now also important to determine what by-products will result from production and what environmental impact there will be. It is possible to have a case in which a less efficient manufacturing process is more profitable due to the value of side products and reduced waste disposal costs.

10. MARKETING

    If there is only one available treatment for a disease, it is only necessary to see that physicians know about it. If there are several competing treatments, there may be quite a bit of marketing done so that physicians will understand the relative merits of each.

11. NON-PERSCRIPTION SALES

    After a large amount of experience under a physicians supervision, a drug may be approved for over-the-counter sales. This is often the biggest profit making end of the pharmaceutical industry.

12. GENERIC PRODUCTION

    Once the chemical patents have expired, a drug can be produced by any manufacturer. Generic drugs are often less expensive for the consumer and yield a low profit margin for the producer. The production of generic drugs favors the most cost effective production process.

REFERENCES

A good book over all, and chapter 7 in particular, is
G. L. Patrick "An Introduction to Medicinal Chemistry" Oxford (1995)

A recent review is

L. M. Balbes, S. W. Mascarella and D. B. Boyd, in "Reviews in Computational Chemistry, Vol. 5" K. B. Lipkowitz, D. B. Boyd, Eds., VCH, 337 (1994)

An introduction to computational techniques is

G. H. Grant, W. G. Richards "Computational Chemistry" Oxford (1995)

A more detailed description of computational techniques is

A. R. Leach "Molecular Modelling Principles and Applications" Longman (1996)

L. Balbes' "Guide to Rational (Computer-aided) Drug Design" is at

gopher://www.ccl.net/00/documents/drug.design.guide

There are many links on Soaring Bear's web page at

http://ellington.pharm.arizona.edu/%7Ebear/

An introduction to structure-based techniques is

I. D. Kuntz, E. C. Meng, B. K. Shoichet Acct. Chem. Res. 27 (5), 117 (1994)

An introduction to De Novo techniques is

S. Borman Chemical and Engineering News 70 (12), 18 (1992)

There is more information about clinical testing at

http://rarediseases.info.nih.gov/ord/ct-info-patient.html

and http://rarediseases.info.nih.gov/ord/ct-about.html

An expanded version of this article will be published in "Computational Chemistry: A Practical Guide for Applying Techniques to Real World Problems" by David Young, which will be available from John Wiley & Sons in the spring of 2001.

A Scrolling History of Computational Chemistry

Allen B. Richon

Introduction

While there were several papers detailing the use of computers in chemistry during the 1960s and 1970s, the first companies organized to address the new areas of chemical databases and molecular modeling were Molecular Design, Ltd. (1978) and Tripos Associates, Inc. (1979) respectively. As the chart below demonstrates, the market grew and evolved continuously since this period and currently is comprised of approximately 20 companies (A horizontal scrolling history and a vertical scrolling history also are available).

There have been several individuals who have contributed to this history and who have corrected some of my mistakes. The author especially wishes to acknowledge Bruce Gelin and Phil Westmoreland for their contributions. If you have logos for any of the companies listed, especially those that were used in the company's early history, I would appreciate hearing from you!

1925

1. Publications

Heisenberg publishes his first paper on quantum mechanics (Z. Phys., 1925, 33, 879).

2. Software & Hardware

3. Computational Chemistry Companies

4. Summary

1926

1. Publications

Schrödinger publishes his first paper on the theory of quantum mechanics (Ann. Phys., 1926, 79, 361).

2. Software & Hardware

3. Computational Chemistry Companies

4. Summary

1931

1. Publications

Pi electron theory postulated by Hückel (Z. Phys., 1931, 70, 204).

2. Software & Hardware

3. Computational Chemistry Companies

4. Summary

1943

1. Publications

2. Software & Hardware

The first computer, the ENIAC (Electronic Numberical Integrator and Computer) is built for the US Army Ordance Department.

3. Computational Chemistry Companies

4. Summary

1946

1. Publications

Westheimer reports the calculation of racemization ratios for ortho-bibromobiphenyls (J. Chem. Phys., 1946, 14, 733).

2. Software & Hardware

3. Computational Chemistry Companies

4. Summary

1950

1. Publications

Roothaan publishes the description of the linear combination of atomic orbitals -molecular orbital - self consistent field (LCAO-MO-SCF) method.

2. Software & Hardware

3. Computational Chemistry Companies

4. Summary

1951

1. Publications

2. Software & Hardware

The first UNIVAC (Universal Automatic Computer) is delivered to the Census Bureau

3. Computational Chemistry Companies

4. Summary

1953

1. Publications

Details of the Pariser - Pople - Parr theory are published (J. Chem. Phys., 1953, 21, 466; J. Chem. Phys., 1953, 21 767).

Metropolis and co-workers describe the application of the Monte Carlo method of simulation to physical chemistry problems (J. Chem. Phys., 1953, 1087, 21).

2. Software & Hardware

3. Computational Chemistry Companies

4. Summary

1955

1. Publications

Scherr reports the first ab initio calculation for a large system, N₂.

2. Software & Hardware

3. Computational Chemistry Companies

4. Summary

1957

1. Publications

Pople publishes details on the application of self-consistent molecular orbital methods to pi electrons (J. Phys. Chem., 1957, 61, 6).

2. Software & Hardware

3. Computational Chemistry Companies

4. Summary

1958

1. Publications

2. Software & Hardware

The first integrated circuit board is constructed by Jack Kilby at Texas Instruments.

The Advanced Research Projects Agency (ARPA) is formed.

3. Computational Chemistry Companies

4. Summary

1961

1. Publications

Hendrickson publishes the results of calculations of relative conformational stabilities of cyclohexane (J. Amer. Chem. Soc., 1961, 83, 5537).

Leonard Kleinrock (MIT) publishes the first paper on packet switching.

2. Software & Hardware

3. Computational Chemistry Companies

4. Summary

1963

1. Publications

2. Software & Hardware

Quantum Chemistry Program Exchange (QCPE) formed at Indiana University to distribute quantum chemistry codes.

3. Computational Chemistry Companies

4. Summary

1964

1. Publications

Hansch and Fujita describe a new approach to analyzing drug actions: QSAR, a quantitative structure activity relationship (Hansch, C and Fujita, T., J. Amer. Chem. Soc., 1964, 86, 1616)

2. Software & Hardware

3. Computational Chemistry Companies

4. Summary

1965

1. Publications

Pople, et. al. publish the CNDO method (Pople, J.A.; Santry, D.P.; Segal, G.A.; J. Chem. Phys.,1965, 43: S129).

The Morgan algorithm is published (Morgan, H.L., "The Generation of Unique Machine Description for Chemical Structures - A Technique Developed at Chemical Abstracts Services", J. Chem. Doc.,1965, 5, 107-113)

2. Software & Hardware

The ORTEP program is announced (Johnson, C.; ORNL-3794, 1965, UC-4 Chemistry. Oak Ridge, Tennessee).

The Chemical Information Program, designed to build a chemical registration and storage system, was initiated at Chemical Abstracts Service.

3. Computational Chemistry Companies

4. Summary

1966

1. Publications

Cyrus Levinthal, et. al. publish paper on the use of molecular graphics and computer simulation (Levinthal, C.; Scientific American, 1966, 214: 42).

2. Software & Hardware

3. Computational Chemistry Companies

4. Summary

1967

1. Publications

The first paper proposing ARPANET is published by Larry Roberts at the DOD's Advanced Research Projects Agency (ARPA)

2. Software & Hardware

3. Computational Chemistry Companies

4. Summary

1969

1. Publications

E.J. Corey and Todd Wipke publish details for the Computer-Assisted Organic Synthesis Planning (CASP) program (Corey, E.J.; Wipke, W.T.; Science, 1969, 166: 178).

Levitt and Lifson report the use of force fields to refine protein conformations derived from experimental data (Michael Levitt and Shneior Lifson; J. Mol. Biol., 1969, 46, 269-279).

2. Software & Hardware

The ARPANET is created by linking computers at Stanford, UCLA, UCSB and Utah.

Ken Thompson, Dennis Ritchie and Joseph Ossanna develop a new operating system, UNIX, for the DEC PDP-7.

Dennis Ritchie and Brian Kernighan create c at Bell Labs.

3. Computational Chemistry Companies

4. Summary

1970

1. Publications

Warshel and Lifson publish a description of the Consistent Force Field (Warshal, A.; Lifson, S.; J. Chem. Phys., 1970, 53: 582-594).

2. Software & Hardware

Boeing announces the maiden voyage of the 747

3. Computational Chemistry Companies

4. Summary

1971

1. Publications

Hendrickson describes a computer assisted synthesis program (Hendrickson, J.B., J. Amer. Chem. Soc., 1971, 93, 6847).

2. Software & Hardware

3. Computational Chemistry Companies

4. Summary

1972

1. Publications

Garland Marshall, et. al. publish a description of the MMS-X program (Marshall, G.R.; Beitch, J.; Ellis, R.A.; Fritsch, J.M.; Diabetes, 1972, 21, Suppl. 2: 506).

The Cambridge Bibliographic file is described (Kennard, O.; Watson, D.G.; Town, W.G.; J. Chem. Doc., 1972, 12: 234-6).

2. Software & Hardware

Ray Tomlinson releases details about a new computer program that can send and receive personalized messages. Electronic mail is born!

3. Computational Chemistry Companies

4. Summary

1973

1. Publications

The Brookhaven Protein Data Bank is announced (Acta. Cryst. B, 1973, 29: 1746).

N.L. Allinger describes the modeling of hydrocarbons with a new force field, MM1 (Allinger, N.L.; Sprague, J.T.; J. Amer. Chem. Soc., 1973, 95: 3893).

2. Software & Hardware

Robert Metcalfe receives his Ph.D. from Harvard University. His thesis describes Ethernet.

3. Computational Chemistry Companies

4. Summary

1974

1. Publications

Robert Langridge, et. al. publish paper on the use of computer graphics to visualize 3-D chemical structures (Langridge, R.; Fed. Proc. Fed. Am. Soc. Exp. Biol., 1974, 33: 2332).

Wipke and Dyott describe SEMA, the Stereochemically Extended Morgan Algorithm (Wipke, W.T.; Dyott, T.M.; J. Amer. Chem. Soc., 1974, 96: 4834).

2. Software & Hardware

Vint Cerf and Robert Kahn develop the concept of connecting networks of computers into an "internet" and develop the Transmission Control Protocol (TCP).

3. Computational Chemistry Companies

4. Summary

1975

1. Publications

Olga Kennard, et. al. publish a description of the Cambridge Crystallographic Data Centre (Chem. Britain, 1975, 213-216).

Harold Scheraga, et. al. publish a description of the ECEPP program (Momany, F.; McGuire, R; Burgess, A; Scheraga, H.; J. Phys. Chem., 1975, 79: 2361) and make the program available through QCPE (The Quantum Chemistry Program Exchange).

The CONGEN program for automated structure generation is described (Carhart, R.E., Smith, D.H., Brown, H., Djerassi, C., J. Amer. Chem. Soc., 1975, 97, 5755).

2. Software & Hardware

Microsoft is founded by Bill Gates and Paul Allen.

3. Computational Chemistry Companies

4. Summary

1976

1. Publications

N.L. Allinger, et. al. release the MM1 program through QCPE (Allinger, N.L.; Quantum Chemistry Program Exchange, 1976, 318).

2. Software & Hardware

3. Computational Chemistry Companies

4. Summary

1977

1. Publications

N.L. Allinger, et. al. publish a description of the MM2 program (Allinger, N.L.; J. Amer. Chem. Soc.,1977, 99: 8127).

Crippen reports the use of distance geometry for calculating conformations (Crippen, G.M.; J. Comp. Phys., 1977, 24: 96-107).

Dewar, et. al. publish details of the MNDO method (Dewar, M.J.S.; Thiel, W.; J. Amer. Chem. Soc.,1977, 99: 4899).

Anthony Hopfinger, et. al. publish a description of the CAMSEQ program, the precursor to Chemlab (Potenzone, R. Jr.; Cavicchi, E.; Weintraub, H.J.R.; Hopfinger, A.J.; J. Comput. Chem., 1977, 1:187).

Martin Karplus, et. al. publish the first molecular dynamics study of a protein (McCammon, J.A.; Gelin, B.R.; Karplus, M.; Nature, 1977 267: 585-590).

The full description of the Brookhaven PDB is published (Bernstein, F.C.; Koetzle, T.F.; Williams, G.J.B.; Meyer, E.F.; Brice, M.D.; Rodgers, J.R.; Kennard, O.; Shimanouchi, T.; Tasumi, M.J.; J. Mol. Biol., 1977, 112: 535).

2. Software & Hardware

3. Computational Chemistry Companies

4. Summary

1978

1. Publications

T. Alwyn Jones, et. al. describe the FRODO program (Jones, T.A.; J. Appl. Crystallogr., 1978, 11:268).

David Pensak, et. al. describe the TRIBBLE program which uses the E&S Multi-Picture System (MPS) for graphics display (Eaton, D.F.; Pensak, D.A.; J. Amer. Chem. Soc., 1978, 100: 7428-7429).

2. Software & Hardware

Digital Equipment Corporation introduces the VAX 11/780.

National Resource for Computation in Chemistry (NRCC) established at Lawrence Berkeley National Laboratory, led by Bill Lester

3. Computational Chemistry Companies

Health Designs, Inc. founded in New York by Kurt Enslein. Primary Product: TOPKAT (toxicology prediction)

Molecular Design Ltd. founded in California by Stuart Marson and Todd Wipke. Primary product: MACCS (chemical databases) which runs on the Prime computer and an IMLAC graphics system.

4. Summary

Companies created during the year: 2

Companies merged/acquired during the year: 0

Total number of companies in the industry group: 2

1979

1. Publications

A description of the NIH Prophet system is published (Rohrer, D.C.; Fullerton, D.S.; Yoshioka, K.;"Computer-Assisted Drug Design", ACS Symposium Series, 1979, 112: 259-279).

Gordon Crippen, et. al. detail distance geometry methods for protein structure calculations (Kuntz, I.D.; Crippen, G.M.; Kollman, P.A.; Biopolymers, 1979, 18: 939 and Havel, T.F.; Crippen, G.M.; Kuntz, I.D.; Biopolymers, 1979, 18: 73 and Crippen, G.M.; J. Med. Chem., 1979, 22: 988).

Lifson and Hagler publish work on a deriving force fields and energy functions to simulate "simple systems" (Lifson, S.; Hagler, A.T.; Dauber, P.; J. Amer. Chem. Soc., 1979, 101: 5111-5121).

Martin Karplus, et. al. describe a new force field for proteins (Gelin, B.R.; Karplus, M.; Biochemistry,1979, 18: 1256).

Marshall, et. al. describe the Active Analog Approach (Marshall, G.R.; Barry, C.D.; Bosshard, H.E.; Dammkoehler, R.A.; Dunn, D.A.; in Computer-Assisted Drug Design. E.C. Olson and R.E. Christofferson, Eds. American Chemical Society Symposium, Vol. 112, Amercian Chemical Society, Washington, DC, 1979, 205-226).

2. Software & Hardware

3. Computational Chemistry Companies

Tripos Associates, Inc. founded in Missouri by Garland Marshall. Primary product: SYBYL which ran on a Gould SEL computer system (molecular modeling, drug design).

4. Summary

Companies created during the year: 1

Companies merged/acquired during the year: 0

Total number of companies in the industry group: 3

1980

1. Publications

MM2/MMP2 with the 1977 force field submitted to QCPE by N.L. Allinger (Quantum Chemistry Program Exchange, 1980, QCPE Program No. 395).

Thomas Dyott, et. al. describe the MOLY program (Dyott, T.M.; Stuper, A.J.; Zander, G.S.; J. Chem. Inf. Comput. Sci., 1980, 20: 28-35).

The Merck MMS is described (Gund, P.; Andose, J.D.; Rhodes, J.B.; Smith, G.M.; Science, 1980, 208:1425-1431).

Wüthrich et. al. publish paper detailing the use of multi-dimensional NMR for protein structure determination (Kumar, A.; Ernst, R.R.; Wüthrich, K.; Biochem. Biophys. Res. Comm., 1980, 95: 1).

The first issue of the Journal of Computational Chemistry is published.

2. Software & Hardware

General Atomic and Molecular Electronic Structure System (GAMESS) developed at NRCC by Michel Dupuis and co-workers.

3. Computational Chemistry Companies

IntelliGenetics founded in California. Primary product: IntelliGenetics Suite (DNA and protein sequence analysis).

4. Summary

Companies created during the year: 1

Companies merged/acquired during the year: 0

Total number of companies in the industry group: 4

1981

1. Publications

Peter Kollman, et. al. publish preliminary description of the AMBER force field for protein/DNA calculations. (Weiner, P.K.; Kollman, P.A.; J. Comp. Chem., 1981, 2: 287-303).

Robert Langridge, et. al. publish description of the MIDAS program (Langridge, R.; Ferrin, T.; Kuntz, I.D.; Connolly, M.L.; Science, 1981, 221, 661).

2. Software & Hardware

IBM introduces its Personal Computer to the market.

3. Computational Chemistry Companies

4. Summary

Companies created during the year: 0

Companies merged/acquired during the year: 0

Total number of companies in the industry group: 4

1982

1. Publications

An algorithm for docking small molecules to receptors (later to become the DOCK program) is published by Irwin Kuntz and colleagues (Kuntz, I.D.; Blaney, J.M.; Oatley, S.J.; Langridge, R.; Ferrin, T.E.; J. Mol. Biol., 1982, 161, 269).

2. Software & Hardware

3. Computational Chemistry Companies

Genetics Computer Group (GCG) created as a part of the University of Wisconsin Biotechnology Center. Primary product: The Wisconsin Suite (molecular biology tools).

Hare Research founded in Washington by Dennis Hare. Primary product: FELIX and DSPACE (NMR structure refinement).

4. Summary

Companies created during the year: 2

Companies merged/acquired during the year: 0

Total number of companies in the industry group: 6

1983

1. Publications

Martin Karplus, et. al. publish description of the CHARMM program (Brooks, B.R.; Bruccoleri, R.E.; Olafson, B.D.; States, D.J., Swaminathan, S. and Karplus, M.; J. Comp. Chem., 1983, 4: 187-217).

Michael Connolly publishes description of a program to calculate and display the solvent-accessible surfaces of proteins and nucleic acids (Connolly, Michael L.; Science, 1983, 221: 709-713 and Connolly, M.L.; J. Appl. Crystallogr., 1983, 16: 548).

W. F. van Gunsteren, et. al. publish description of molecular dynamics of proteins using GROMOS program (van Gunsteren, W.F.; Berendsen, H.J.C.; Hermans, J.; Hol, W.G.J.; Postma, J.P.M.; Proc. Natl. Acad. Sci., 1983, 80: 4315).

2. Software & Hardware

The Compact Disk (CD) is launched.

3. Computational Chemistry Companies

Chemical Design Ltd. founded in Oxford, UK by Keith Davies. Primary product: Chem-X (molecular modeling, drug design).

Hypercube Inc. founded in Waterloo, Canada by Neil Ostlund. Primary product: HyperChem (PC-based molecular modeling).

New Methods Research Inc. (NMRi) founded in New York by George Levy. Primary product: NMR-1 (NMR spectroscopy acquisition and analysis).

4. Summary

Companies created during the year: 3

Companies merged/acquired during the year: 0

Total number of companies in the industry group: 9

1984

1. Publications

Peter Kollman, et. al. publish description of the AMBER program (Weiner, S.J.; Kollman, P.A.; Case, D.A.; Singh, U.C.; Ghio, C.; Alagona, G; Profeta, S.; Weiner, P; J. Amer. Chem. Soc., 1984, 106:765-784).

Svante Wold publishes the details of Partial Least Squares (PLS), a new method of data analysis which facilitates the derivation of linear equations from data tables that have more columns than rows (Wold, S., Ruhe, A., Wold, H., and Dunn, W.J. III; SIAM J. Sci. Stat. Comput., 1984, 5, 735).

2. Software & Hardware

Jon Postel's Domain Name System (DNS) is placed on-line.

The Macintosh is announced.

3. Computational Chemistry Companies

BioDesign, Inc. founded in California by Barry Olafson, Stephen Mayo, and William Goddard. Primary product: BioGraf (molecular modeling, protein design).

Biosym Technologies founded in California by Arnold Hagler and Donald MacKay. Primary product: Insight/Discover (molecular modeling, protein design).

Evans & Sutherland Computer Corporation establish the Molecular Sciences Group and obtain MOGLI from Shell Research.

Polygen Corporation founded in Massachusetts by Frank Momany, Jeffrey Wales, Jean-Loup Fayolle, and Andy Ferrara. Primary product: QUANTA/CHARMm (molecular modeling, protein design).

4. Summary

Companies created during the year: 4

Companies merged/acquired during the year: 0

Total number of companies in the industry group: 13

1985

1. Publications

Peter Goodford publishes a paper detailing the use of probe-interaction grids for SAR studies on fields derived from 3D geometries (Goodford, P.J.; J. Med. Chem., 1985, 28, 849).

2. Software & Hardware

3. Computational Chemistry Companies

ORAC Ltd. founded in the UK by Glen Hopkinson. Primary product: ORAC/OSAC (chemical and reaction databases).

Serena Software founded in Indiana by Kevin Gilbert. Primary product: PCModel/GMMX (molecular modeling).

4. Summary

Companies created during the year: 2

Companies merged/acquired during the year: 0

Total number of companies in the industry group: 15

1986

1. Publications

The first presentation of CONCORD made at the 1986 ACS Meeting in Anaheim (Rusinko, A. III; Skell, J.M.; Balducci, R.; Pearlman, R.S.; "CONCORD: Rapid Generation of High Quality Approximate 3-Dimensional Molecular Coordinates", Abstracts of the 192nd American Chemical Society Meeting, Anaheim, CA, 1986).

2. Software & Hardware

NSFnet debuts

3. Computational Chemistry Companies

Amoco Technology Corporation acquires IntelliGenetics.

Biosym Technologies announces the first computational chemistry consortium to derive potential energy functions.

CAChe Scientific founded in Oregon by George Fabel and George Purvis as a subsidiary of Tektronix. Primary product: CAChe (Macintosh-based molecular modeling).

Cambridge Scientific Computing founded in Massachusetts by Stewart and Michael Rubenstein. Primary product: ChemDraw (Macintosh-based chemical structure drawing and molecular modeling).

Columbia University releases first version of Clark Still's MacroModel program.

4. Summary

Companies created during the year: 3

Companies merged/acquired during the year: 1

Total number of companies in the industry group: 18

1987

1. Publications

Robert Pearlman publishes the first description of CONCORD ("Rapid Generation of High Quality Approximate 3D Molecular Structures", Pearlman, R.S.; Chemical Design and Automation News,1987, 2: 1,5-7).

The Journal of Computer-Aided Molecular Design is published.

2. Software & Hardware

The manual for the THOR, GENIE, and MERLIN software from the Pomona MedChem project are described (Weininger, D., Weininger, A., and Leo, A.J., MedChem Software Manual, Release 3.53, Medicinal Chemistry Project, Pomona College, Claremont, CA, 1987).

Larry Wall releases a new programming language, the Practical Extraction and Report Language (Perl).

3. Computational Chemistry Companies

Biostructure SA founded in France by Jean-Marie Lehn, Bernard Roques, Dino Moras, Pierre Oudet, and Gerard Bricogne. Primary product: BioGromos/BioExplore (molecular modeling, protein design).

Daylight Chemical Information Systems Inc. founded in California by Arthur and David Weininger and Yosef Taitz. Primary product: THOR/MERLIN/SMILES (chemical database).

First commercial release of CONCORD

Evans & Sutherland Computer Corporation acquires Tripos Associates, Inc.

Gaussian, Inc. founded in Pennsylvania by John Pople to be sole distributor for the Gaussian program.

Health Designs Inc. releases the first version of TOPKAT.

Maxwell Communications Corporation acquires Molecular Design Ltd.

Proteus Molecular Design LTD founded in Cheshire, UK by Kevin Gilmore, John Pool, and Barry Robson.

4. Summary

Companies created during the year: 4

Companies merged/acquired during the year: 2

Total number of companies in the industry group: 20

1988

1. Publications

2. Software & Hardware

A new program, an Internet computer virus designed by a student, infects 6,000 military computers in the US.

Richard Cramer publishes the first description of CoMFA, a QSAR technique that explicitly incorporates 3D geometries (Richard D. Cramer, III, David E. Patterson, and Jeffrey D. Bunce, J. Amer. Chem. Soc., 1988, 110, 5959-5967).

3. Computational Chemistry Companies

4. Summary

1989

1. Publications

Allinger et. al, publish the first descriptions of the MM3 program (Allinger, N.L.; Yuh, Y.H.; Lii, J.-H.;J. Am. Chem. Soc., 1989, 111: 8551, 8566, 8576).

2. Software & Hardware

3. Computational Chemistry Companies

BioCAD Corporation founded in California by Terry Smith, Michael Jacobi, and Steve Teig. Primary product: Catalyst (2D and 3D chemical database).

Cambridge Molecular Design founded in Cambridge, UK by Patrick Coulter. Primary product: Cerius family of products (molecular modeling, materials design).

GCG becomes a private company.

Oxford Molecular Group, Ltd. (OMG) founded in Oxford, UK by Anthony Marchington, David Ricketts, James Hiddleston, Anthony Rees, and W. Graham Richards. Primary products: Anaconda, Asp, Cameleon and others (molecular modeling, drug design, protein design).

Polygen announces investment position by IBM.

4. Summary

Companies created during the year: 3

Companies merged/acquired during the year: 0

Total number of companies in the industry group: 23

1990

1. Publications

Clark Still, et. al. publish the description of MacroModel (Mohamadi, F; Richards, N.G.J.; Guida, W.C.; Liskamp, R; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T. and Still, W.C.; J. Comp. Chem., 1990, 11: 440-467).

The first volume of Reviews in Computational Chemistry is published.

2. Software & Hardware

3. Computational Chemistry Companies

Molecular Applications Group founded in California by Michael Levitt and Chris Lee. Primary product: Look, SegMod (molecular modeling, protein design).

Schrödinger, Inc. founded in California by Richard A. Friesner and William Goddard. Primary product: PS-GVB (ab initio quantum mechanics).

4. Summary

Companies created during the year: 2

Companies merged/acquired during the year: 0

Total number of companies in the industry group: 25

1991

1. Publications

2. Software & Hardware

The research institute in Geneva (CERN) announces creation of the protocols which make-up the World Wide Web.

The Gopher program is released by the University of Minnesota

3. Computational Chemistry Companies

BioDesign changes name to Molecular Simulations Inc. (MSI).

Cray Research announces UniChem.

MSI acquires Cambridge Molecular Design.

MSI and Polygen Corporation merge to form a new company, MSI, with headquarters in Massachusetts and Pasadena.

Wavefunction, Inc. founded in California by Warren Hehre. Primary product: Spartan (ab initio quantum mechanics).

4. Summary

Companies created during the year: 2

Companies merged/acquired during the year: 2

Total number of companies in the industry group: 25

1992

1. Publications

Bruce Gelin publishes the first edition of MMCC Results, a survey of the computational chemistry literature. The issue surveys 30 journals that report studies in the field.

2. Software & Hardware

3. Computational Chemistry Companies

Synopsys founded in England by Glen A. Hopkinson, Keith Harrington, and Paul Hoyle. Primary product: The Accord series of chemical information tools.

Autodesk, Inc. licenses exclusive rights to Hypercube's products.

Biosym Technologies acquires Hare Research.

Corning, Inc. acquires Biosym Technologies.

Evans & Sutherland acquires NMRi.

Maxwell Communication acquires ORAC Ltd. and merges them with MDL.

Semichem, Inc. founded in Kansas by Andrew Holder. Primary product: AMPAC (semiempirical quantum mechanics).

4. Summary

Companies created during the year: 2

Companies merged/acquired during the year: 3

Total number of companies in the industry group: 24

1993

1. Publications

2. Software & Hardware

The Supercomputing Institute (NCSA) at the University of Illinois releases Mosaic.

3. Computational Chemistry Companies

MicroSimulations Inc. founded in New Jersey by Weili Cui. Primary product: AccuModel and PowerFit (Windows- and Macintosh-based molecular modeling).

Beilstein created as a sales and marketing group for the Beilstein Institute.

Q-Chem, Inc founded in Pittsburg, PA by Carlos Gonzalez, Peter Gill and Benny Johnson.

MDL files Initial Public Offering as MDL Information Systems,Inc.

Oxford Molecular Group acquires Biostructure SA.

4. Summary

Companies created during the year: 3

Companies merged/acquired during the year: 1

Total number of companies in the industry group: 26

1994

1. Publications

2. Software & Hardware

Netscape Communications Corporation founded and releases Navigator.

3. Computational Chemistry Companies

Autodesk, Inc. returns exclusive rights for HyperChem to Hypercube, Inc.

Interactive Simulations founded in San Diego, California by Mark Surles. Primary product: Sculpt (molecular modeling, drug design, protein design).

Joseph Votano establishes ChemSoft, a computer consulting firm in Lexington, MA. The company becomes SciVision, a Windows-based chemistry software company.

MDL acquires Occupational Health Services.

MSI acquires BioCAD Corporation.

Oxford Molecular Group announces exclusive representation for AMBER.

Oxford Molecular Group acquires IntelliGenetics.

Oxford Molecular Group releases Initial Public Offering on the London Stock Exchange.

Tripos Associates, Inc. spun-off by E & S as a publicly traded company, Tripos, Inc.

4. Summary

Companies created during the year: 2

Companies merged/acquired during the year: 2

Total number of companies in the industry group: 26

1995

1. Publications

2. Software & Hardware

NSFnet is retired. Several private companies assume responsibility for the network backbones in the US. Universities announce creation of vBNS.

Sun launches java. Netscape and Sun release JavaScript

Microsoft releases Internet Explorer.

3. Computational Chemistry Companies

Cambridge Scientific Computing changes name to CambridgeSoft Corporation.

Corning merges Biosym with MSI to form an independent company, MSI, with headquarters in California.

MolSoft LLC is founded in New Jersey.

Oxford Molecular Group acquires CAChe Scientific.

Oxford Molecular group acquires the RS³ product from PSI.

4. Summary

Companies created during the year: 1

Companies merged/acquired during the year: 2

Total number of companies in the industry group: 25

1996

1. Publications

N.L. Allinger et. al. publish first description of MM4 (Allinger, N.L.; Chen, K.S.; Lii, J.H.; Nevins, N.; J. Comp. Chem., 1996, 17: 642, 669, 695, 730).

2. Software & Hardware

3. Computational Chemistry Companies

Chemical Computing Group founded in Quebec, Canada. Primary products Molecular Operating Environment (MOE) and Scientific Vector Language (SVL).

Oxford Molecular Group acquires the MacVector product from Eastman Kodak.

Oxford Molecular Group acquires the Unichem product from Cray Research.

Oxford Molecular Group acquires Health Designs, Inc.

Spotfire founded in Sweden by Chris Ahlberg. Primary product is Spotfire Pro, a data visualization program.

4. Summary

Number of companies created during the year: 1

Number of companies merged/acquired during the year: 2

Total number of companies in the industry group: 24

1997

1. Publications

2. Software & Hardware

3. Computational Chemistry Companies

MDL Information Systems, Inc. agrees to be acquired by Reed-Elsevier publishers.

Hypercube, Inc. relocates to Gainesville Florida.

Molecular Simulations files registration statement with the SEC to offer stock.

OpenEye Scientific Software founded in Santa Fe, New Mexico by Anthony Nicholls. Primary products are dedicated to the analysis of large chemical databases.

Oxford Molecular Group acquires the Genetics Computer Group and MLR Automation

LION Bioscience AG founded in Heidelberg, Germany

Columbus Molecular Software founded in Columbus, Ohio by Paul Blower, Glenn Myatt, and Wayne Johnson. Primary product is LeadScope, a structure-based data mining program.

Camitro founded in Menlo Park, CA. Primary products are focused on computational ADME and Toxicity models.

Partek Inc. is formed in St. Louis, Missouri by Tom Downey. Primary product is Partek Pro, a data visualization and analysis program.

4. Summary

Number of companies created during the year: 5

Number of companies merged/acquired during the year: 2

Total number of companies in the industry group: 27

1998

1. Publications

2. Software & Hardware

3. Computational Chemistry Companies

Molecular Simulations purchased by Pharmacopeia

Oxford Molecular Group acquires Chemical Design Ltd.

MicroSimulations acquired by orCAD

MacroModel (Columbia University) and Schrödinger merge

BioReason is formed in Santa Fe, New Mexico by Susan Bassett, John Elling, and Tony Rippo. The primary products are dedicated to data mining and activity prediction models.

4. Summary

Number of companies created during the year: 1

Number of companies merged/acquired during the year: 4

Total number of companies in the industry group: 24

1999

1. Publications

2. Software & Hardware

The Napster file sharing system appears on the internet.

3. Computational Chemistry Companies

Interactive Simulations acquired by Reed-Elsevier publishers.

COSMOlogic GmbH & CoKG, spun off from Bayer by Andreas Klamt. COSMOlogic offers computational chemistry software and services for the thermodynamics of liquids.

Materials Design s.a.r.l., in France and its sister company SciCo Inc. in California started by Erich Wimmer

Molecular Applications Group sells its assets to Celera.

Scitegic formed in San Diego, CA by Matthew Hahn and David Rogers

4. Summary

Number of companies created during the year: 3

Number of companies merged/acquired during the year: 2

Total number of companies in the industry group: 25

2000

1. Publications

2. Software & Hardware

3. Computational Chemistry Companies

Columbus Molecular Software changes its name to LeadScope

Synopsys Scientific Systems purchased by Pharmacopeia

Oxford Molecular Group purchased by Pharmacopeia

Afferent Systems purchased by MDL Information Systems

4. Summary

Number of companies created during the year: 0

Number of companies merged/acquired during the year: 2

Total number of companies in the industry group: 23

2001

1. Publications

2. Software & Hardware

3. Computational Chemistry Companies

Camitro purchased by ArQule

Trega Biosciences purchased by Lion Biosciences

Pharmacopeia combines Molecular Simulations, Synopsys Scientific Systems, and Oxford Molecular Group into a new subsidiary, Accelrys

4. Summary

Number of companies created during the year: 0

Number of companies merged/acquired during the year: 2

Total number of companies in the industry group: 21