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Performance
of 50 Completed ATP Projects
Status
Report - Number 2
NIST SP 950-2
Chapter
3 - Biotechnology
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Molecular
Simulations, Inc.
(Formerly Biosym Technologies, Inc.)
Powerful Software for Designing
New Molecules and Therapeutic Drugs
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| The
traditional route to discovering new therapeutic drugs and other useful
chemicals should probably be called “semiautomated serendipity.”
In the search for new drugs, hundreds of synthetic chemicals and natural
substances are put through a long series of trials, starting with
effectiveness tests in cell-based assays and concluding with toxicity
and effectiveness trials in laboratory animals and, finally, humans.
At each stage, the vast majority of substances fail the test and are
discarded. |
COMPOSITE
PERFORMANCE SCORE
(Based on a four star rating.)
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| The geometrical
and electron structure of a siliceous CHA-framework material isotopological
with the mineral chabazite. Zeolites and related crystalline microporous
solids such as chabazite have industrially useful separative and catalytic
properties that are determined by both the micropore architecture
and the nature of active sites. |
Using Mathematics
to Find New Drugs
This ATP project with Molecular Simulations, Inc. (MSI), a small San Diego
company that had 170 employees when the project began, combined applied
mathematics and computer programming to develop new methods for simulating
molecular structures and reactions. The technology is more efficient than
conventional molecule-design techniques, a quality that translates into
speedier product development and lower costs.
The ATP-funded effort
led to new understanding of density functional theory (DFT), a quantum
mechanics method. Most work to understand molecules is mathematical, and
DFT is a relatively new form of applied mathematics previously not widely
used to simulate molecules. Researchers successfully demonstrated the
applicability of DFT to the study of biochemical systems, the backbone
of drug research, showing that DFT is as accurate as other approaches
and considerably less expensive.
Applications in New
Drugs and Petrochemicals
Prior to its ATP award, MSI was already developing, marketing and supporting
a suite of software tools suitable for computing the behavior and properties
of molecules. The
suite includes tools for bioinformatics, combinatorial library optimization,
determination of protein structures from amino acid sequences, and structure-
and analog-based rational drug design. The ATP project enabled MSI researchers
to incorporate the new DFT knowledge into several of these tools. Most
MSI software users benefit from access to several different tools and
will use more than one of them in a given study.
The geometry of
a heme complex, optimized by first principles density functional methods
implemented in the program DMol, using technology developed under
ATP sponsorship. In this molecule, which contains more than 150 atoms,
the central iron atom (central, dark red) is coordinated by four nitrogen
atoms (blue) of the heme group, and a dioxygen molecule (red). |
One of the first MSI
tools to be enhanced with the DFT technology was Turbomole, a computer
software application that integrates a database of atomic functions, a
modern user-interface, and mathematical tools like DFT. The computer program
calculates tables of molecular characteristics and generates a three-dimensional
structure of the molecule that can be viewed by molecular graphics.
Another tool upgraded
with the new technology is DMol, a quantum chemistry program that enables
users to make reliable, quantitative predictions about molecular systems.
The ATP-funded technology—a DFT-based component of the program—decreases
the cost of these types of computation, potentially reducing the cost
of designing new molecules. The ATP-funded technology is being used experimentally
in petrochemical research, and it has potential applications in biotechnology,
rational drug design, microelectronics, and industrial fine chemicals
research.
Benefits to Companies
and Consumers
Because the MSI software is relatively low-cost, enters the discovery
and development cycle close to its beginning, and is used by research
and development personnel in large organizations, the benefits to the
users of the software can be large relative to what MSI earns through
software licenses. Such benefits will accrue to chemical, petrochemical,
pharmaceutical, and biotechnology companies, as well as to companies in
other industries that use MSI software incorporating the ATP-funded technology.
Benefits will also accrue to people who use therapeutic drugs and other
products made by companies using the new technology. In addition, scientists
worldwide might benefit from a database of molecular structures developed
under the ATP award — MSI is considering making the database available
on the Internet.
Electron density
isosurface of a zirconocene complex, color-coded by electrostatic
potential, as computed by the DMol program. The geometrical and electronic
structures in metallocene complexes govern the nature of the polyolefin
products produced when single site catalysts of this type are used
to catalyze olefin polymerization. |
MSI reports that the
ATP funds enabled it to complete research on the DFT technology and incorporate
the results into its software products some 18 months earlier than it
would otherwise have been able to do. The company, its customers in the
pharmaceutical and materials industries, and their customers have all
benefited. The project also facilitated the dissemination of new knowledge,
particularly via the many scientific papers that were published about
the ATP-funded technology.
Company Grows, Announces
IPO, is Acquired at a Large Premium
Since the end of the ATP project in May 1995, the com-pany has grown at
a cumulative annual rate of about 20 percent. In February 1997, it filed
a Form S1 with the Securities and Exchange Commission announcing its intention
to conduct an Initial Public Offering of stock, and noted that it expected
to raise about $35 million by selling about half of the stock in the company.
In February 1998, the company and Pharmacopeia, Inc., announced that Pharmacopeia
would acquire MSI. The acquisition was finalized in June 1998 in a transaction
valued at approximately $140 million.
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Project
Highlights
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PROJECT:
To develop density functional theory (DFT), a type of first principles
quantum mechanics, for use in the development of new therapeutic
drugs and other substances, an application that is expected to achieve
substantial time and cost savings.
Duration: 6/1/1992 — 5/31/1995
ATP Number: 91-01-0224
FUNDING (in
thousands):
| ATP |
$1,442
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44%
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| Company |
1,867
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56%
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| Total |
$3,309
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ACCOMPLISHMENTS:
MSI successfully demonstrated the applicability of DFT to the study
of biochemical systems and developed software that employs DFT to
efficiently calculate molecular structures and energies. The software
was used to study biochemically relevant systems. It proved as accurate
as other approaches,
yet much less expensive. Also, the company:
- prepared
more than 30 technical papers on the ATP-funded technology for
publication in professional journals or presentation at conferences;
- implemented
a highly accurate way of applying DFT in the company’s Turbomole
computer software product;
- expanded
its physical plant to accommodate larger R&D and
production facilities;
- was a finalist
for a Computerworld Smithsonian Award, the 1996 Innovator Medal;
andn has grown at a cumulative annual rate of about 20 percent
since the end of the ATP project in May 1995.
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COMMERCIALIZATION
STATUS:
Commercialization is in progress. MSI incorporated the ATP-funded
technology into the company’s existing Turbomole software package,
which has been distributed to more than 100 sites. The ATP-funded
technology has also been incorporated into MSI’s quantum chemistry
workbench software. Benefits from the ATP-funded technology are
already accruing to users of MSI software, as well as to users of
products developed with the software.
OUTLOOK:
Expectations for this technology and the company are strong. The
technology has been incorporated into commercially distributed products
that are being used extensively by a relatively small, yet global,
community of scientists in academic, industrial, and governmental
laboratories for rational drug design and petrochemical research.
It has potential applications in biotechnology, microelectronics,
and industrial fine chemicals research.
Composite
Performance Score:
COMPANY:
Molecular Simulations, Inc.
(MSI; formerly Biosym Technologies, Inc.)
9685 Scranton Road
San Diego, CA 92121
Contact: John M. Newsam,
Phone: (619) 546-5391
Number of employees: 170 at project start, 292 at the end
of 1997
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of Contents or go to next section.
Date created: April
2002
Last updated:
April 12, 2005
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