Advanced Structural Chemistry and Molecular Modelling

Course objectives

The objective of the course is to introduce the participants to different experimental and theoretical methods for determination and analysis of three-dimensional structures of biologically important molecules. The application of these methods in the study on relationships between molecular structure and biological activity are dealt with in detail.

General contents and topics

Nearly all drugs exert their effect by an interaction with a biological macromolecule, i.e. by activation of a receptor or by inhibition of an enzyme. This interaction involves a specific molecular interaction between the drug (the ligand) and the macromolecule (often a protein). Today, considerable information has been accumulated about the relationships between structure and activity for most types of drugs. Nevertheless, knowledge about the molecular interactions between the drug molecule and the macromolecule in the organism is still limited in most cases.

The most important experimental method for determination of structures of organic molecules is X-ray crystallography. By X-ray crystallographic methods it is possible to determine high-resolution three-dimensional structures of small molecules as well as macromolecules such as proteins.

The term, molecular modelling, comprises a variety of computer-based methods used to construct three-dimensional models of chemical compounds, and to calculate a number of different characteristics for the compounds (e.g. shape, flexibility, charge distribution, lipophilicity). Computer graphics is very important for visualisation of the molecules and their characteristics.

Molecular modelling makes it possible to construct models of already known molecules, but also unknown or not yet synthesised molecules can be investigated. With molecular modelling it is possible to study the relationships between molecular structure and various properties, and to assist in design of compounds with preselected properties.

Molecular modelling and computer graphics are powerful tools in the study of the relationships between molecular structure and biological activity, and thus essential in the process of rational drug design. Molecular modelling has become an indispensable part of modern medicinal chemistry and during the last decade the methods have been implemented in most pharmaceutical companies.

During the course a number of examples of biological (pharmaceutical) importance will be presented and discussed with special emphasis on the following topics:

• Molecular structures and 3D-databases: X-ray crystallography (theoretical background and quality evaluation), crystallographic databases (Cambridge Structural Database and Protein Data Bank), other 3D-databases, predictive methods (from sequence to three-dimensional structure and homology building).
• Molecular mechanics-based methods: Different force fields (potential functions, parameters, limitations), energy minimisation, charges, electrostatics and molecular dynamics simulations.
• Structure-activity analyses: Conformational analysis, conformational energies, conformational search methods, template fitting and pharmacophore identification.
• Protein-ligand interactions: Binding energies, docking, structure-based molecular design, de novo design.

General information

The course will be organised as a course of two weeks' duration and will comprise 20 lectures and approx. 40 hours' practical exercises and discussions. Lecture notes and selected scientific publications will be used. There will be no formal examination, but to complete the course satisfactorily the participants need to take active part in the course. Participants who have completed the course satisfactorily will be granted a certificate.

Duration

11 to 22 March 2002.

Course weight

0.083 STÅ (STÅ = student full-time equivalent) = 4.98 ECTS (European Credit Transfer System)

Course director

Associate Professor Flemming Steen Jørgensen, Department of Medicinal Chemistry at The Royal Danish School of Pharmacy

Course fee

Total: DKK 11,700 (including lunch),
of which operating costs amount to: DKK 1,700.
An additional amount for study materials: DKK 500.

Closing date for application

1 February 2002.

Course capacity

20 participants.

N.B.

The course addresses PhD students with an MSc degree in biochemistry, biology, chemistry, pharmacology or pharmacy, or research scientists in the pharmaceutical industry.