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Chem. Int., Vol. 17, No. 6, pp. 212-214, 1995

Working Party on Medicinal Chemistry Curriculum

Syllabus for a Short Postgraduate Course
in Medicinal Chemistry

C. Robin Ganellin

A compilation of subject headings for 24 lectures is provided as the basis of a short course for teaching the elements of medicinal chemistry. This course is aimed at organic chemists who have recently entered the pharmaceutical industry and wish to become conversant with medicinal chemistry. Such courses have been successfully running as 1-week summer schools in the UK, USA, and Netherlands.


In developed countries, the pharmaceutical industry is one of the major employers of organic chemists, espe-cially in research and development. Many prospective chemist employees are hired to become medicinal chemists or to fit into a team of scientists engaged in the search for a new drug which it is hoped will become a new medicine.

The newly appointed chemists have to discover how to synthesize new molecules for biological testing. This may make full demands on their synthetic skills, but it may not be fully satisfying intellectually. It will certainly not provide research medicinal chemists with a fully re-warding intellectual experience if they cannot appreci-ate fully the reasons for making these compounds. Consequently, they will have to learn to communicate with biological scientists, to converse with biochemists, pharmacologists, toxicologists, and pharmacists in or-der to be actively involved in drug design. They will want to decide which compounds to make, as well as appreciating how to make them.

Soon the novice medicinal chemist will come up against the mystery of trying to relate chemical struc-ture to biological activity. In this connection, colleagues will mention the importance of lipophilicity, hydrophobic interactions, quantitative structure-activity relationships (QSAR), molecular modeling, electrostatic energy potentials, and so on. These may be unfamiliar words and new concepts that will be difficult to acquire and take time to comprehend. Few organic chemists will have taken courses in drug design during their uni-versity training. Some may have taken courses in natural product chemistry or bioorganic chemistry but these topics will be of little help in tackling structure-activity analysis. What then can be done to assist the new em-ployee enter this new field of endeavor?

There is debate among medicinal chemists about the best way of teaching the subject. The Medicinal Chemistry Section Committee [1] of IUPAC has set up a Working Party to consider a Medicinal Chemistry Curriculum. The Committee sent a questionnaire, regarding academic training for medicinal chemists, to major research pharmaceutical companies in a variety of countries. One set of replies, mainly from Germany, Japan, and the UK, has been analyzed and the results published.[2] Responses from Italy and the USA, which were solicited subsequently, were similar to those received earlier. The overwhelming response (>90%) was that companies seek to hire the best organic chemists and whether they have, or have not, received some education in medicinal chemistry was of secondary importance. This confirms the impression that there is a strong need to introduce the novice medicinal chemist to further education in medicinal chemistry. The Committee has responded by proposing the subject matter for a one-week school.

Some pharmaceutical companies are aware of these problems and run their own courses in drug design; of-ten they encompass some introductory pharmacology and biochemistry that relates directly to their own research areas of interest. It was in recognition that there may exist such a need that the Royal Society of Chemistry (RSC) introduced, as an experiment in 1979 a one-week Summer School [3] in medicinal chemistry as part of their general program of one week courses in specialist topics.

One cannot, of course, teach a whole subdiscipline in one week. However, if the topics are carefully chosen to represent the core of the subject, and if it is well lectured by active practitioners, it should be possible to get across most of the main concepts and increase the awareness and understanding of the specialist language. Such a short course can provide a basic framework, the sense of direction of which the chernist can then build upon if prepared to put in the necessary reading and study. With the above thoughts in mind, the second Summer School in medicinal chemistry was or-ganized by Dr A. M. Roe and Dr C. R. Ganellin in 1981.

What then should constitute the syllabus for such a one-week school? The approach taken was to focus on the core discipline of medicinal chemistry, namely structure-activity analysis and to take in related concepts and provide a few examples. Because of time constraints, there was little background history included and almost no discussion of diseases as targets for research.

The course was also directed to graduate or postdoctoral organic chemists who had recently entered the pharmaceutical industry or were contemplating doing so in the near future. The course was successful and established the blue-print for a syllabus that has subsequently been run ning, in alternate years, at the University of Kent, Canterbury, under the auspices of the RSC.[4] Always fully subscribed (100 places for "students") with about 20 lecturers (mostly from industry), it has clearly demonstrated its utility. To emphasize this point, it is noteworthy that similar "schools" have subsequently been established in other countries. In the USA (at Drew University. Madison, NJ, annually since 1987, 100 places), in the Netherlands (at Leiden, Amsterdam in Noordwijkerhout since 1992, 20 places) and most recently in Switzerland (Leysin, since 1994, 20 places). The exact content of these different schools varies according to the lecturers and the perception of the organizers, but basically they have a very similar composition.

The author has been approached many times about the best course content for a medicinal chemistry school, especially by medicinal chemists from other countries who wish to see something of a similar nature established in their own country. It seems of interest and appropriate therefore, to share the thoughts of the IUPAC Medicinal Chemistry Section Committee with a wider audience and to solicit comment from interested chemists.

A week's course is encapsulated in the following list of subject headings representing approximately 24 lectures. By and large, they also reflect the most popular topics suggested by the company responses to the questionnaire, [2] namely subjects such as biochemistry, drug metabolism, pharmacokinetics, pharmacology and physiology, computer modeling, and QSAR. However, additional components for drug design are included, such as the importance of physiological concepts, operational strategies, prodrugs, and case studies of drug discovery. Naturally, these subjects can all easily be expanded to fill several weeks if desired.


Syllabus for a 1-week school as an introduction to medicinal chemistry

Introduction

  • Research Strategy

Biological targets

  • Lead generation/sources for drugs;
  • Receptors and drug-receptor interactions;
  • Enzymes and design of inhibitors;
  • Ion channels, membranes, and transporters;
  • Second messengers.

Bioassay

  • Screening methods and the information that they provide;
  • Determining activity: principles of pharmacological assay, biological variation (and the need for statis-tics), in vitro and in vivo methods.

Structure-activity methods

  • Physicochernical concepts, including pKa, solvent partition, Hammett, H-bonding, steric parameters;
  • QSAR, parameterization, and computer-assisted lead optimization, statistical methods;
  • Molecular modeling, energy calculations, and molecular graphics;
  • Operational strategies in molecular modification, pharmacophore identification, conformational restriction, isosterism, lipophilicity control, solubilization;
  • Development of a lead compound (a tutorial exercise).

Biodisposition and implications

  • Pharmacokinetics, concepts, parameters, and modeling;
  • Drug metabolism;
  • Prodrugs;
  • Molecular toxicology and avoidance of toxic intermediates.

Case studies
Three case studies of drug discovery and design. Four lectures selected from the following possibilities:

  • Bioorganic chemistry;
  • Chirality in drug action;
  • Clinical pharmacology;
  • Combinatorial chemistry;
  • Drug delivery;
  • Ethical considerations;
  • Molecular biology; role in drug discovery;
  • Nucleotides;
  • Patents;
  • Peptidemimetics;
  • Regulatory procedures.

References and notes

  1. Membership of the Committee comprises Professor J. G. Topliss (President), Dr N.Koga (Vice-President), Professor W. D. Busse (Secretary), Professor C. G. Wermuth (Past-President), Professor C. R. Ganellin (Chairman of the Working Party), and Professor L. A. Mitscher. Additionally involved were Dr P. Lindberg (Astra, H�ssle, M�Indal, Sweden), Professor G. Tarzia (University of Urbino, Italy), Dr J. Ide (Sankyo, Tokyo, Japan), and Professor A. Monge (University of Navarro, Spain).
  2. W. D. Busse and C. R. Ganellin, Views From Industry on the Medicinal Chemistry Curriculum: Answers to a Questionnaire. In Trends in Drug Research, Ed. V. Claassen, Pharmacochemistry Library, 20, Elsevier, Amsterdam, 1993, pp. 305-315.
  3. Held at University of Bradford and organized by Professors J. M. Midgley and J. B. Stenlake.
  4. Inquiries should be directed to Ms. L. A. Hart, The Royal Society of Chemistry, Burlington House, Piccadilly, London WIV 0BN, England, UK.

 


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