New Methods

The experimental and computational methods used in biostructure-based drug designs are constantly evolving. Here, we will only mention a few of the methods that have and are expected to have a great impact on the design process.

The availability of an increasing number of experimentally determined structures of relevant targets is crucial. Crystallization, data collection, and structure determination processes are today partially or fully automated. Centers for high throughput determination of 3D structures have been established in several countries. These developments and initiatives are reflected in an increase in the number of experimentally determined structures deposited at the Protein Data Bank. Many pharmaceutical companies also have in-house groups doing structure determinations, but the number of structures determined here is difficult to estimate.

Computationally, the developments are also considerable. Improved methods for determination of models of structures based on structures of related proteins, i.e., homology modeling or comparative modeling, are being developed. Faster computers allow longer and thereby more realistic simulations of proteins where flexibility and solvation can be considered. Ligand docking programs are being improved by considering not only the flexibility of the ligand but also the flexibility of the protein. The prediction of binding energies have always been a problem in docking methods, but improved quantum mechanics-based or quantum mechanics-derived methods combining speed and accuracy are being developed. Better description and handling of the solvation vs. desolvation processes are also crucial for the correct prediction of binding affinities.

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