Powerful Programs Simplify Molecular Modeling

The first molecular modeling software, developed at Columbia University in the mid-1960s by the late Cyrus Levinthal (see page 28), was capable of displaying and manipulating complex molecules in two dimensions. By the mid-1970s, at the University of California, San Francisco, molecular modeling had been taken to a new level by Robert Langridge, Michael Connelly, and Peter Coleman, with more sophisticated, three-dimensional graphics and new manipulative capabilities, including the ability to portray an atom's volume in three-dimensional space rather than as a ball-and-stick figure. But at a minimum cost of $500,000, this software was out of reach for most researchers. Today, however, for less than a tenth of that cost, researchers can obtain molecular modeling software with high-resolution graphics. These packages can compute and illustrate the structure of molecules from any angle, perform quantum mechanical calculations, calculate a wide range of molecular properties, and identify structure-activity relationships. Molecular modeling programs are proving invaluable to chemists, bio- chemists, pharmacologists, virologists, molecular biologists, and other researchers interested in simulating interactions of important molecules in order to study the relationships of structure to activity. William C. Ripka, vice president of pharmaceutical research at San Diego-based Corvas Biopharm-aceuticals Inc., a small company that develops therapies to combat thrombosis, works closely with the molecular modeling software Corvas uses in drug development research. According to Ripka, even though the marketplace has seen the introduction of an increasing number of competing products, the category must continue to expand in order to satisfy the needs of today's scientists using molecular modeling in drug design. BioDesign Inc. 199 S. Los Robles Ave. Suite 540 Pasadena, Calif. 91101 (818) 793-3600 Product: POLYGRAF; $50,000-$60,000; $75,000 for complete workstation BIOSYM Technologies Inc. 10065 Barnes Canyon Rd. San Diego, Calif. 92121 (619) 458-9990 Product: Insight II; $30,000-$60,000 per workstation Cambridge Scientific Computing Inc. 875 Massachusetts Ave. Cambridge, Mass. 02139 (617) 491-6862 Products: Chem3D; $595. Chem3D Plus; $895 Molecular Design Ltd. 2132 Farallon Dr. San Leandro, Calif. 94577 (415) 895-1313 Product: CHEMLAB-II; $60,000-$95,000 Polygen Corp. 200 Fifth Ave. Waltham, Mass. 02254 (617) 890-2888 Product: QUANTA; $50,000-$100,000 Tektronix Inc. Box 500 Mail Stop 13-400 Beaverton, Oreg. 97077 (503) 627-3737 Product: CAChe; $12,000-$46,000 (higher-priced packages include computer hardware) Tripos Associates Inc. 1699 South Hanley Rd. St. Louis, Mo. 63144 (314) 647-1099 Products: SYBYL; approximately $25,000 and up. Alchemy II; IBM-compatible: $750; Macintosh: $950 Like many other medicinal chemists in both academic and industrial settings, Ripka uses molecular modeling software packages for both their computational and their graphic capabilities. A typical computational task is calculating a molecule's three-dimensional orientation based on the interaction of its atomic components. Displaying this three-dimensional representation and manipulating the structure by rotating, translating, or changing its features are examples of graphic tasks. Because these modeling activities can save hundreds of hours of "wet-lab" tests, molecular modeling has become an important tool in increasing the speed and efficiency of basic scientific research. In the late 1970s, several large pharmaceutical operations, including de- partments at Merck Sharp & Dohme, Abbott Laboratories, and E.I. Du Pont de Nemours & Co. Inc., invested substantial amounts of money in molecular modeling software packages, says Ripka, who headed Du Pont's drug design team at the time. Now, the amount required to purchase molecular modeling packages has plummeted from about $500,000 to $25,000-$95,000 for software that typically runs on mainframe computers or smaller workstations, depending on the software and the amount of customized features. Among the industry leaders is Molecular Design Ltd., a San Leandro, Calif.-based company that distributes molecular modeling packages such as CHEMLAB-II, a VAX-based system with a variety of applications, widely used by pharmaceutical firms. Molecular modeling programs are also available for PCs. Relatively inexpensive packages are available, such as Alchemy II, distributed by Tripos Associates Inc. of St. Louis. At the high end of the spectrum is the CAChe Worksystem, from Tek-tronix Inc., based in Beaverton, Oreg. The CAChe system includes an accelerator board that increases more than 20-fold the speed of the Macintosh computer it runs on. Software strong in computation tends to be weak in graphics, and vice versa, says Ripka. "It would be a disservice to say there is one overwhelming favorite [molecular modeling software package]. The problem is they all have interesting features, but they don't have all of the basics." Multiple Programs Needed To compensate for the limitations of the different molecular modeling packages on the market, Ripka and other scientists heavily involved in drug design use more than one program. Ripka uses two separate software packages, each with different strengths and each requiring an investment of approximately $50,000. QUANTA, offered by Polygen Corp. of Waltham, Mass., has strength in computation, while Insight II, from BIOSYM Technologies Inc. of San Diego, has strong graphics capabilities. "It would be optimal if both functions were [well-developed] in a single program," Ripka says. Many of these companies are trying to address this shortcoming. For instance, according to Ripka, Polygen originally focused on computational capability, and the company continues to lead the pack in this area. Now, however, Polygen is striving to improve QUANTA's graphics capabilities as well. In addition, says Ripka, the company is sensitive to feedback from users, adding new features and new methodologies according to customers' suggestions. Ripka has been using molecular modeling programs to conduct his research for the past 15 years. David Spellmeyer, whom Ripka recruited to Du Pont's drug design team before leaving the Wilmington, Del.-based company last year for his current job at Corvas, also works extensively with these packages. Spellmeyer joined Du Pont in December 1989, fresh from a postdoctoral fellowship in molecular modeling at UC-San Francisco. In his position at Du Pont, Spellmeyer receives information from biologists and chemists working in the laboratory on a project. He then tries to make sense of these biological and chemical data at several different levels, such as determining interactions of molecules with receptor sites and enzymes. For example, using molecular modeling software and information provided by chemists, Spellmeyer constructs an allegedly active conformation for a particular compound. Then, he might suggest chemical alterations to the compound, designed to increase its activity. He is able to make these suggestions based on theoretical manipulations of the compound using the software. Biologists working on the project provide information on the compound's activity to support or negate Spellmeyer's suggestions. The modeler, the chemist, and the biologist interact closely to ensure that the most active compound is created. Molecular modeling software "provides me with a set of tools which enable me to do what Du Pont is paying me to do, research," Spellmeyer says. "Instead of writing programs, it frees me up to do real research," such as conducting conformational analyses of molecules. Like Ripka, Spellmeyer uses two software packages: Tripos' SYBYL and QUANTA. "SYBYL is extremely good for small molecules," he says, "while QUANTA is good for proteins." He adds, however, that both companies are trying to broaden the utility of their packages. "The big disadvantage in using two programs is cost," he says. "Each does something the other doesn't do as well. The trade-off is functionality. If you were really, really rich, you'd have them all." According to Spellmeyer, many molecular modeling programs now available, including SYBYL, have graphical interfaces especially useful for the bench chemist or nonexpert because they are so user-friendly. If you don't do any modeling for several months, he says, it's easy to get back in the swing of things with a menu that "helps you get through [the program] without having to remember everything." Microcomputers, which have had two-dimensional graphic capability for many years, have recently begun to accommodate software with three-dimensional modeling capability. One popular molecular modeling package for the Macintosh is the CAChe system, offered by Tektronix Inc. Unlike the programs described earlier, CAChe is primarily for the experimental, rather than the theoretical, scientist. The basic CAChe system includes a custom accelerator board that increases the computing capabilities of the Macintosh, providing 21 million instructions per second (MIPS) of com- puting power. CAChe builds and displays three-dimensional representations of molecules using molecular mechanics. It calculates minimum energy conformations, electronic density, and atomic volumes of molecules. CAChe can also compare biologically active molecules with other potential structures. By overlapping two structures, a researcher can compare attributes of an active structure with those of the unknown compound, a capability that is useful in designing new drug entities. Philip Fuchs, a professor of chemistry at Purdue University, West Lafayette, Ind., is a CAChe enthusiast. "The [CAChe] graphic capabilities are excellent for teaching undergrads," Fuchs says. "It creates good pictures, and you can see the chemistry really happening in 3-D and in color, rather than in black and white." CAChe includes computational packages, such as Molecular Mechanics, which uses a classical force field method to refine molecular structures, and ZINDO, useful for the study of transition metals and organometallic compounds. PC Programs While CAChe's price and capabilities place it in the mainframe class of modeling packages, personal computer owners have more affordable molecular modeling software options as well. Chem3D, available from Cambridge Scientific Computing Inc. of Cambridge, Mass., runs on all current Macintosh computers. This package enables the user to view, rotate, and animate models of more than 2,000 atoms in real time. It includes built-in substructures for creating complex molecules and enables researchers to compare molecules using least squares fitting. Chem3D can import files in several different formats, including ChemDraw, Cambridge Scientific's chemical graphics package. Chem3D Plus, designed for high-performance Macintosh computers such as the Macintosh II, also includes energy minimization and color modeling. Tripos has also developed three-dimensional molecular modeling software for the personal computer. Alchemy II, available in both Macintosh II- and IBM-compatible versions, allows the chemist to build molecules using an expandable library of molecular fragments and a built-in energy minimizer. Least squares fitting can be performed to compare two molecules. In addition, Alchemy II can animate displays, so that the user can rotate molecules on the screen in three dimensions. The IBM-compatible version of Alchemy II is designed to interface with STN Express, a software package from the American Chemical Society's Chemical Abstracts Service that allows it to access on-line databases providing three-dimensional coordinates of more than 4 million substances. According to Willis Hammond, research associate in the math and simulation department of Allied-Signal Inc. in Morristown, N.J., advances in molecular modeling software for polymer and materials science are much more recent than those in medicinal chemistry and molecular biology. A number of companies, including Molecular Design, BIOSYM, Polygen, and Tripos, developed software for modeling polymers and other materials in the late 1980s. Many polymer modeling programs include crystal builders and amorphous polymer packages, both of which are important functions in commercial polymer research. In addition, these programs can predict mechanical features by calculating how the polymers react to various environments with varying temperature or pressure. Allied-Signal participated in early, premarket testing of POLYGRAF, a polymer modeling package offered by BioDesign Inc. of Pasadena, Calif. The firm is also involved in testing BIOSYM and Polygen products. Software companies typically fund development of new products by setting up consortia with major industrial firms, in which the firms pay a fixed subscription rate to participate in initial research. For example, Allied-Signal, Exxon Corp., Goodyear Tire & Rubber Co., Amoco Corp., and Du Pont are among the 30 members of BIOSYM's polymer consortium. This entitles them to "first crack at the research results," according to Hammond, as well as a reduced rate if they choose to keep the products. Twenty-five years after it was first developed, molecular modeling software is enabling more and more researchers to accomplish tasks that might have taken weeks or even months in a matter of hours on a computer screen. Software companies are working to better integrate computational and graphics functions, increasing the amount of information that can be gleaned from the laboratory. Lisa Simon is a freelance writer based in Philadelphia. David Nugiel is a research scientist at E.I. Du Pont de Nemours & Co. Inc. in Wilmington, Del.

Powerful Programs Simplify Molecular Modeling

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