Fpocket: an open source platform for ligand pocket detection

Abstract

Background: Virtual screening methods start to be well established as effective approaches to identify hits, candidates and leads for drug discovery research. Among those, structure based virtual screening (SBVS) approaches aim at docking collections of small compounds in the target structure to identify potent compounds. For SBVS, the identification of candidate pockets in protein structures is a key feature, and the recent years have seen increasing interest in developing methods for pocket and cavity detection on protein surfaces.

Results: Fpocket is an open source pocket detection package based on Voronoi tessellation and alpha spheres built on top of the publicly available package Qhull. The modular source code is organised around a central library of functions, a basis for three main programs: (i) Fpocket, to perform pocket identification, (ii) Tpocket, to organise pocket detection benchmarking on a set of known protein-ligand complexes, and (iii) Dpocket, to collect pocket descriptor values on a set of proteins. Fpocket is written in the C programming language, which makes it a platform well suited for the scientific community willing to develop new scoring functions and extract various pocket descriptors on a large scale level. Fpocket 1.0, relying on a simple scoring function, is able to detect 94% and 92% of the pockets within the best three ranked pockets from the holo and apo proteins respectively, outperforming the standards of the field, while being faster.

Conclusion: Fpocket provides a rapid, open source and stable basis for further developments related to protein pocket detection, efficient pocket descriptor extraction, or drugablity prediction purposes. Fpocket is freely available under the GNU GPL license at http://fpocket.sourceforge.net.

Figure 1

Fpocket (A), Tpocket (B) and Dpocket (C) flowcharts.

Figure 2

Examples of pocket detection using fpocket. top left: Rank 1 pocket on the alpha amylase (7TAA). Acarbose in surface/coloured/opaque representation, the binding site is represented as yellow transparent hull. Alpha sphere centres are depicted as small red points. top right: Rank 1 pocket of the HIV1 Protease DMP450 complex (PDB Code: 1DMP). DMP450 is depicted in grey CPK representation and the binding pocket as transparent hull. Superposed are other known inhibitors (yellow) binding in the same pocket (PDB Codes: 1Z1H, 2UY0, 2P3B). Alpha sphere centres are depicted as small interconnected spheres. Alpha spheres and the pocket are coloured according to polar (orange) and apolar (white) character. bottom left: Cyclooxygenase-2 indomethacin binding site: (red) pocket identified by fpocket,(yellow) pocket identified by PocketPicker. bottom right: Acetylcholinesterase rank 1 predicted binding pocket by fpocket. Red: pocket of the holo structure with tacrine (1ACJ), yellow: pocket of apo structure (1QIF). Pockets are represented as a hull resulting from the union of the alpha spheres.

Figure 3

Pocket detection limits. Left: Example of PDB entry 1esa. A large part of the ligand is outside the pocket detected by fpocket. Despite this fact, a criterion such as the PocketPicker criterion would accept the pocket as successfully identified, and the Mutual Overlap criterion not. Right: Example of PDB entry 1w1p. The identified pocket is large compared to the ligand. Its centre of mass is too far from any atom of the ligand for the Pocket Picker criterion to accept it as successfully identified. Ligands are represented using a ball and sticks representation. Alpha sphere centres are represented as small spheres, and their envelope is depicted in brown.