The course will revolve around six topics that all relate to each other: Drug Design and Drug Docking; Force Fields; Homology Modelling; Structure Validation; Molecular Dynamics; Sequence Alignment.

Figure 3. We start this summary picture series with Drug Design. Drug Design has drug docking as a big sub-topic. Drug design and drug docking are the largest fields in terms of employing chemists.

Figure 4. Drug design makes extensive use of Force Fields. Several of those Force Fields will be discussed in this course.

Figure 5. Virtual screening is the term used for testing for a large number of small molecules if they can be docked in a pocket in a target. These targets normally are proteins. If the structure of the protein has not been solved yet by either Xray crystallography or NMR spectroscopy, then we need to predict it. This is best done with Homology Modelling. Homology Modelling makes extensive use of Force Fields, too.

Figure 6. Both Homology Modelling and Drug Design / Drug Docking are forms of professional gambling. They provide predictions. So you expect more errors than when the structure of the target or the target - drug complex are solved experimentally. So, validation of the results is even more important than in the case of experimental structures. The arrow is a bit hidden, but structure, model and complex validation uses more Force Fields than any other topic in this course.

Figure 7. Proteins are not hard as rocks but actually rather flexible. So, if you see a protein structure, you see one possible structure that accidentally could be crystallized. If your drug seems not to fit in this conformation, then you might discard it as a lead for drug design. But if another conformation would be ideal for this drug, then you actually discard a potentially very good opportunity. This is where Molecular Dynamics can help. With Molecular Dynamics you can predict how a protein moves around in its conformational space.

Figure 8. Homology Modelling uses a rather extensive Force Field, and we will spend an entire seminar to explain its intricacies.

Figure 9. Homology Modelling uses Molecular Dynamics to improve the quality of the model, and Molecular Dynamics often needs Homology Models to work on in Drug Design. Alternate conformations of the target protein must be validated too.

Figure 10. Homology Modelling requires that the homology between your protein of interest and the homologous protein with know structure gets worked out at the level of the individual amino acids. This is called sequence alignment . Sequence alignments, though, can provide much more information and a few examples will be presented in the Sequence Alignment seminar.