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Learning objectives
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.
Content
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. 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.
Learning objectives
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.
Content
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. 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.
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