Fragment based drug discovery starts with screening libraries of fragment-sized organicmolecules for binding to the target protein. The fragments cluster at binding hot spots,the most important regions for drug discovery, and can be extended into larger andhigher affinity ligands. The protein-mapping program FTMap is a computationalanalogue of fragment screening experiments. Acpharis has licensed the docking engineof FTMap and developed the ATLAS software as an updated version of the FTMapprogram. While ATLAS is a useful tool for identifying binding sites and predictingdruggability, with proper development it can provide much more valuablecharacterization of both the binding site and the preferred fragments. The major goal ofthis proposal is to develop a software package based on ATLAS that, starting from thestructure of a target protein, will be able to reliably screen very large virtual compoundlibraries for potential hits. To achieve this major goal we propose the followingdevelopments. Our first goal is to identify regions on the target protein that havepreferences for binding specific functional groups and to identify a set of boundfragments that can be used as seeds for 2D and 3D screening. This will involve foursteps. (1) Developing a higher accuracy scoring function to enable discrimination amongdifferent functional groups. (2) Obtaining generalized pharmacophore information byiterative mapping, where the initial mapping, indicating preferences for certain functionalgroups, will be followed by more focused mapping using probes containing similarfunctional groups; (3) designing basic and extended fragment libraries for the two stepsof mapping; and (4) improving the functional characterization of the site by addingbinding information from the PDB using a novel pocket similarity algorithm. Onceextended pharmacophores are established, we plan to use ensembles of bindingfragments as pseudo-compounds to seed a ligand-based shape-matching searchmethod to screen large libraries of compounds based on molecular similarity. Thetraditional 2D similarity search will be modified to account for the additional 3Dinformation provided by the mapping. This will enable screening larger libraries and willyield more specific results than the existing 2D ligand based tools. Once we have a setof potential ligand hits, we will perform template based ligand placement to produce avariety of possible poses, and to score the refined poses.
Public Health Relevance Statement: Computational solvent mapping program ATLAS is a useful tool for identifying binding
sites of protein targets and predicting their druggability. With proper development it can
provide much more valuable characterization of both the binding site and the preferred
fragments. The goal of this proposal is to develop a software package based on ATLAS
that, starting from the structure of a target protein, will be able to reliably screen very
large virtual compound libraries for potential binding hits.
Project Terms: <3-D><3D><3-Dimensional>
