Computational Methods to Support Fragment‐based Drug Discovery

The current computational methods available to fragment-based drug discovery (FBDD) are not without their own challenges and limitations. With the exception of the development of fragment screening libraries, all methods discussed in this chapter require knowledge of the protein three-dimensional structure. Knowledge of the binding site size, shape, and chemical functionalities can be used throughout the FBDD process, steering fragment library design, assessing druggability of a binding site, and extending core fragments. The application of computational methods to FBDD has been without problems; in others, most notably, fragment docking, modifications are required to properly address the unique energetics and dynamics of fragment binding. Fragment expansion is by necessity addressed using computational methods and is often approached as a combinatorial problem.