What are the primary limitations for homology modeling in drug design today?
As mentioned before, the quality and, thus, the utility of homology models is highly dependent on the sequence identity between the target and the template protein. The primary limitation for a broader use of homology models in drug design is the poor quality of models that are based on a lower sequence identity to the template protein. In many cases such models are not sufficient for detailed predictions on how small-molecule ligands bind and where to modify them to obtain a stronger interaction with the target protein. What would you like to see improved over the next few years? The quality and the reliability of the structures. That is one thing that is limiting the applicability of the method. And also the inclusion of protein flexibility, like induced-fit phenomena. For example, Schrödinger has recently released a program that deals with induced-fit phenomena. Do you use that software? Yes. We see induced-fit phenomena in many of our protein-structure based design projects. The mo
