“Throughout the pharmaceutical and biotech industries, it has become increasingly clear in recent years that there just aren’t enough chemists trained in combinatorial chemistry,” says David Hangauer of New York State’s University at Buffalo (UB). Although combinatorial chemistry short courses are increasingly available (see below), industry would prefer to hire chemistry graduates already knowledgeable in the theory and practice of combichem to reduce the time needed for in-house training. Students with this background could have a significant advantage in the job market, particularly a “cooler” job market in a slowing economy. Hangauer said that one major drug firm began an in-house tutorial program for its chemists. However, the course was expensive, and the time required significantly reduced R&D productivity.

Training in combinatorial chemistry may become increasingly common, in part because of the conclusions of a survey-based report on Ph.D. education (www.phd-survey.org). “The training doctoral students receive is not what they want, nor does it prepare them for the jobs they take,” says the 60-page report, At Cross Purposes: What the experiences of today’s doctoral students reveal about doctoral education (1).

For starters
Hangauer’s one-semester course at UB is an example of how the new movement to teach combinatorial chemistry in the classroom has developed. (For detailed information, visit http://wings.buffalo.edu/academic/department/pharmacy/ mch/public_html/combichem.html.) Hangauer says that his own combichem research and his knowledge of the needs of the pharmaceutical industry (he worked for Merck for 10 years before joining UB) led him to develop the UB combinatorial chemistry course. “Clearly, it was time for academia to start turning out chemistry graduates with these skills,” says Hangauer.

After searching for information on the Internet and talking to colleagues, Hangauer decided that no courses were available on combinatorial chemistry and that he would have to design his own.

Specialized laboratory equipment is required to practice combinatorial chemistry, which means that funding is needed to purchase the equipment or make it in university shops. UB received a $50,000 grant from the Camille and Henry Dreyfus Special Grant Program in the Chemical Sciences for the laboratory portion of the course and $15,000 from UB’s Office of the Provost.

The course, called simply Combinatorial Chemistry, is offered as Medicinal Chemistry 427 (for undergraduate students) and Medicinal Chemistry 527 (for graduate students). The course is divided into two modules: a 1-credit-hour lecture module, which is taught in the first third of the semester, and a 2-credit-hour laboratory module, which is taught in the last two-thirds. Students can take only the lecture module if they want an overview of combinatorial chemistry. The laboratory module is intended to provide hands-on introductory training in combichem techniques for those who may wish to seek employment in the pharmaceutical or biotechnology industries as chemists. Thus, the focus is primarily on the medicinal and synthetic organic chemistry aspects of combinatorial chemistry. The course was immediately popular, with students filling both course sections to capacity.

The restricted availability of specialized combinatorial chemistry equipment and supplies limits enrollment in the 2-credit-hour laboratory course. The laboratory module accepts students achieving a grade of B– or better in the lecture module. Even with this requirement, the instructor must approve each student’s participation in the laboratory course.

Hangauer also teaches a related graduate-level, 3-credit-hour course, Medicinal Chemistry 525, Structure-Based Design of Ligands and Combinatorial Libraries, which provides an intensive theoretical foundation in combinatorial chemistry.

“The two courses go hand-in-hand,” says Hangauer. “The first teaches you how to design the combinatorial libraries, while the second teaches you how to synthesize the libraries.” The focus of Medicinal Chemistry 525 is on the principles of drug design. The first half of the course covers the theory and methods of modeling ligand:protein complexes using protein X-ray or NMR structures as an experimental foundation. Subjects include molecular mechanics calculations, computer graphics and ligand docking techniques, de novo generation of new ligands, and the thermodynamics of ligand binding in water. The individual ligand design methods are then used to evaluate different methods of designing combinatorial libraries of ligands. Hangauer uses contemporary drug targets to illustrate these methods. The second half of the course begins with hands-on training in the molecular modeling software package SYBYL using Silicon Graphics terminals. Each student has an individual project designing a combinatorial library of ligands from a protein structure. To develop analytical and oral presentation skills, students present a critical evaluation of a current combinatorial chemistry research paper in which the methods covered in this course were a key component.

Expanding the menu
Few other universities have courses focused solely on combinatorial chemistry. One that does is Northeastern University, which offers a lecture course, Chemistry 4388, Combinatorial Chemistry, as an introduction to the subject. The course covers

• peptide chemistry and its application to the discovery of ligands for biological receptors;
• combinatorial chemistry in drug discovery, materials science, and catalysis;
• methods of solid-phase synthesis;
• automation in synthesis, analysis, and purification;
• data handling;
• design of diverse screening libraries; and
• drug design.

To enroll, students need a sound knowledge of basic organic and analytical chemistry.

Arno F. Spatola at the University of Louisville has developed a course entitled Combinatorial Chemistry and Molecular Diversity. First presented to senior undergraduates and first-year graduate students in spring 1996, this course appears to be the earliest complete combinatorial chemistry course offered by a college or university. Its emphasis is on drug discovery. The course has featured guest lectures by experts on different aspects of combinatorial chemistry. Several industrial firms have provided funding for the course.

Some universities, while not offering complete combichem courses, are taking other approaches to including combinatorial chemistry in the curriculum. At Rutgers University, for example, combinatorial chemistry is part of the Advanced Medicinal Chemistry II graduate-level course. At Rensselaer Polytechnic Institute, CHEM-4330, Drug Discovery, includes combinatorial chemistry, chip-based automated synthesis, and high-throughput screening. A laboratory is part of this 4-credit-hour course. At Georgetown University, combinatorial chemistry is included in a graduate-level course, Chemistry 572, Bioorganic Chemistry. However, the time available for combinatorial chemistry is limited because the course also includes rational drug design, antigene and antisense strategies, and drug delivery.

Combinatorial chemistry is briefly discussed in the second semester of a sophomore organic chemistry honors course taught by Matthew Sigman at the University of Utah. At the University of Pennsylvania, solid-phase synthesis and combinatorial chemistry in drug discovery are covered in an advanced organic chemistry course. The Special Topics in Synthetic Chemistry courses and Advanced Topics in Organic Chemistry include combinatorial chemistry as one of a limited number of topics covered.

Simple experiments not requiring specialized equipment have been used to illustrate the basic principles of combinatorial organic chemistry to students. David Burney and Stephen Starnes at Texas Tech University have taught second-semester organic chemistry students using the Fischer esterification reaction, a common experiment in sophomore organic chemistry laboratories. Parallel combinatorial chemistry is illustrated by having each student synthesize a different ester. The principles included in the class experiment are simultaneous synthesis of a large number of compounds, a selective assay for a desired activity (identifying the compound having the characteristic odor of oil of wintergreen), and an algorithm for identifying the active chemical structure (2).

Online and short courses
For those not fortunate enough to be able to take a combinatorial chemistry course as a full-time student, GeneEd E-Learning offers an online combinatorial chemistry short course as part of a suite of biopharmaceutical courses (www.GeneEd.com). Prerequisites are an undergraduate science or science-related degree, or familiarity with the life sciences through industry experience.

As would be expected from a short course, the subject material is introductory. The course focuses on the use of combinatorial chemistry for drug discovery. The instructor, Sunil Maulik of DoubleTwist.com (formerly named Pangea Systems) and a co-founder of GeneEd.com, covers the requirements for performing combinatorial chemistry, the design and synthesis of combinatorial libraries, and molecular diversity analysis as applied to antibodies, peptides, nucleic acids, and small molecules. He also discusses assaying issues related to high-throughput screening, particularly at the microscale.

Molecular Simulations, Inc., offers a three-day workshop on the basics of quantitative structure–activity relationships (QSARs) and combinatorial library design, from initial library specification to library analysis techniques (www.msi.com/about/events/training). On the first day, an overview of QSAR methods and descriptors is presented with a focus on combinatorial chemistry methods. The next two days cover methods of selecting chemically diverse subsets from a virtual library, techniques for lead explosion after initial SAR data have been determined, methods for library–library comparison, and several approaches to hole filling of an existing library.

In 2000, ACS offered a short course, Combinatorial Chemistry: Solid and Solution Phase Synthesis, coordinated with its first ACS ProSpectives Conference, 21st Century Chemical Synthesis (Tucson, AZ, April 9–11). This short course was also offered at PittCon 2001; it will be offered in Boston August 16–17, immediately after the Drug Discovery Technology 2001 conference, and in Chicago August 24–25 as one of the short courses associated with the ACS national meeting. This lecture course provides a state-of-the-art introduction to combinatorial chemistry. Subjects discussed include tools and techniques available for library synthesis, instrumentation for solid- and solution-phase synthesis, and applications and synthetic strategies used in library design. The instructors are Aubrey Medonca, director of marketing and product manager of IRORI, and Michael Organ, who founded the combinatorial chemistry facility of York University in Toronto. In May, a longer version of the course, which included a laboratory segment, was given at the University of Texas, Austin, using local instructors.

The business perspective
A course taught at Rutgers University, Management of Science and Technology I: Strategic Management of Technology, considers combinatorial chemistry from a business perspective. The course discusses the issue of reducing the drug development time-to-market and then looks at how combinatorial chemistry is changing the discovery process. How it affects the roles of experience and experimentation, as well as the risks involved, are among the issues addressed. In an aspect that has career management implications, the course explores the issue of how combinatorial chemistry affects different stakeholders in the development process (chemists trained in combinatorial synthesis and high-throughput screening techniques, traditionally trained chemists, other research scientists, and middle and senior managers).

Speaking of the curriculum at his university, Hangauer says, “As the need accelerates, both undergraduates and graduate students at UB who have had both the lecture course and the lab in combinatorial chemistry should be attractive potential employees for the pharmaceutical and biotech industries.” The same is true of all universities offering chemistry degrees. With increased use of combinatorial chemistry in catalysts, materials science, and other chemical technology areas, Hangauer’s comment may also become increasingly relevant to employment in the entire chemical and allied products industry.

References

1. Golde, C. M.; Dore, T. M. At cross purposes: What the experiences of today’s doctoral students reveal about doctoral education; Pew Charitable Trusts: Philadelphia, 2001.
2. Birney, D. M; Starnes, S. D. Parallel combinatorial esterification: A simple experiment for use in the second-semester organic chemistry laboratory. J. Chem. Educ. 1999, 76, 1560.

John K. Borchardt is a science writer based in Houston. Send your comments or questions regarding this article to mdd@acs.org or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.