The course objectives are to introduce participants to different experimental methods and methods in molecular modelling (or computational chemistry) 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. The course will provide the participants with the opportunity to apply molecular modelling methods to their own research problems.

Nearly all drugs exert their effect by an interaction with a biological macromolecule, i.e. by activationof 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. NMR spectroscopy and molecular modelling methods represent alternative methods for the determination of three-dimensional structures and biologically relevant targets.

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: Experimental methods (X-ray crystallography and NMR spectroscopy), computational methods (homology building) and 3D-databases including crystallographic databases (Protein Data Bank),.

·        Molecular mechanics-based methods: Different force fields (potential functions, parameters, limitations), energy minimisation, charges, electrostatics and molecular dynamics simulations.

·        Quantum mechanics methods: Approximations, basis set, determination of properties (e.g. structures, energies, charges).

·        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.

·        ADME (absorption, distribution, metabolism and excretion) modelling.

The practical exercises will include tutorials aimed at learning specific tasks and projects based on the participants own research activities.

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.

Based on individual performance, assessed by active participation, and a short report (max. 2,500 words) on a selected subject, a pass/fail is given by the course directors.

30 January to 10 February 2012.

6 ECTS credit points (European Credit Transfer System).

150 working hours (50 for preparation, 60 for course, and 40 for report and evaluation).

Professor Flemming Steen Jørgensen and Associate Professor Lars Olsen, Department of Medicinal Chemistry at the Faculty of Pharmaceutical Sciences, University of Copenhagen.

Total course fee: DKK 16,000 (including lunch),

of which operating costs: DKK 3,300.

1 December 2011.

20 participants.

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

The course will only be held in English.