ProCare – A Computer Vision Approach to Align Protein Cavities. Application to Fragment-Based Drug Design
Creators: name: Eguida, Merveille
name: Rognan, Didier
Publisher: name: Zenodo
Year: 2020
Subjects: Binding site comparison
Point cloud
Shape
Pharmacophoric features
Protein subpocket
Fragments
Cheminformatics
GCC2020

description: In this talk at the GCC 2020, we present a point cloud method to align and compare protein pockets and subpockets. The access to protein 3D structures enables to guide the design of bioactive molecules. As part of the different possible strategies to arrive at this end, comparison of protein binding pockets can provide a wealth of information to design ligands for apo protein cavities, can help to repurpose existing drugs, to detect potential off-targets, or on the contrary to direct multi-target drug design [1]. Although several tools to compare binding sites are described in the literature [2], not all of them are freely accessible. Besides, most of available methods perform global comparison which can hinder any local similarity detection. Finally, while some tools are alignment-free, methods yielding 3D alignments can facilitate the interpretation of results. These considerations motivated us to develop ProCare, an open source point cloud alignment method for binding site comparison [3], inspired from 3D point set registration [4]. Two protein cavities to be compared were each represented by a set of 3D points regularly filling the cavity, each point being labelled by a pharmacophoric property [5]. Each point was then described by a local fingerprint (c-FPFH) encoding the spatial relation of points [6] and pharmacophoric properties in the neighborhood [3]. Thereafter a Random Sample Consensus algorithm was used to find associations between points in the two sets, based on a nearest neighbor search in the fingerprint space and topological constraints. An alignment is estimated to superpose the associated points, then refined with an Iterative Closest Point algorithm. Finally, the proposed alignment is scored with a Tversky metric evaluating whether points of the same properties were aligned. The code is available at https://github.com/kimeguida/ProCare. ProCare was successfully applied to globally compare protein cavities. In comparison to a global alignment method, it showed better performance to precisely align fragment local cavities onto larger cavities. In a retrospective screening of ~34000 fragment subpockets on larger cavities from 3 different proteins, ProCare could correctly position subpockets as well as their corresponding fragments which were true bioisosteres of substructures of the co-crystallized ligands [3]. Although the method can improve, ProCare is already offering possibilities to assist drug design and can be applied to apo protein cavities. [1] Ehrt, C.; Brinkjost, T.; Koch, O. J. Med. Chem. 2016, 59 (9), 4121–4151. [2] Ehrt, C.; Brinkjost, T.; Koch, O. PLoS Comput. Biol. 2018, 14, e1006483. [3] Eguida, M.; Rognan, D. J. Med. Chem. 2020, 63 (13), 7127–7142. [4] Zhou, Q.-Y.; Park, J.; Koltun, V. 2018, arXiv:1801.09847. [5] Desaphy, J.; Azdimousa, K.; Kellenberger, E.; Rognan, D. J. Chem. Inf. Model. 2012, 52 (8), 2287–2299. [6] Rusu, R. B.; Blodow, N.; Beetz, M. 2009, IEEE Int. Conf. Robot. Autom. 2009, 3212–3217.