E-FTMap: A Protein Structure Based Pharmacophore Identification Server for Guiding Fragment Expansion
Omeir Khan, George Jones, Dima Kozakov, Dmitri Beglov, Diane Joseph‐McCarthy, Sándor Vajda
Abstract
In fragment-based drug design (FBDD), libraries of low molecular weight compounds are screened against a receptor. Due to their size, fragment hits typically bind with weak affinities by forming a handful of highly efficient interactions with the receptor. Such fragment hits must be expanded into more potent lead compounds in order to achieve higher binding affinities. Approaches for expanding fragments to leads include growing-the iterative expansion of the scaffold, and merging-the linking of two fragment hits. In both cases the design can be facilitated by information on the ligand binding preferences of the target protein. Here we describe a protocol for fragment expansion using E-FTMap, an automated web server that identifies important pharmacophore binding regions within a binding site of proteins using the receptor structure alone. E-FTMap distributes 119 small organic probes across a binding site, identifies energy minima in which similar probes bind, and clusters probes by their atom types to identify regions which preferably bind specific atom types. Unless a priori known, the binding site for this analysis can be identified by our FTMap server that uses only 16 probes to find binding hot spots that are generally preferable for ligand binding, whereas the subsequent use of E-FTMap provides atom-specific information. The utility of E-FTMap as a tool for guiding the expansion of fragments into higher affinity binders is demonstrated by its application to 17 proteins that have been targeted by FBDD. The E-FTMap webserver is publicly accessible at https://eftmap.bu.edu/.