Table 2.

Methods to compare protein cavities.

Year	Name	Detection	Principle	Scoring	Evaluation Datasets
2002	CavBase [17]	LIGSITE [12]	Clique detection in graphs of pseudoatoms	Overlap of surface grid points, RMSD	Cofactor sites, kinases, serine proteases
2002	eF-site [109]	Ligand Databases	Clique detection in graph of surface normal vectors and electrostatic potentials	Normalized and weighed contributions of vectors angles, potentials, distances	Phosphate sites, antibodies, PROSITE classes
2003	SuMo [110]	Ligand	Incremental match of triplets of pseudocenters	Count of matches, RMSD, composite of Euclidean and density distances	Protease catalytic sites, lectines
2004	SiteEngine [18]	Ligand	Match of triplets of points by hashing	Hierarchical scoring: count of matches, RMSD, overlap of patches, local shape	Cofactors, steroids, fatty acid sites, catalytic triad in proteases
2004	SitesBase [111]	Ligand	Match of triplets of points	Count of matches, RMSD	Cofactors, phosphate sites
2007	Ramensky et al. [112]	Ligand	Clique detection in graph of atoms	Dice similarity of matches	Diverse
2008	Binkowski et al. [113]	CAST [6] Ligand	Comparison of pairwise distance histograms	Kolmogorov–Smirnov divergence, overlap of volume, RMSD	Cofactor sites, HIV proteases
2008	PocketMatch [19]	Ligand	Comparison of sorted pairwise distances	Normalized count of matches	Diverse, SCOP classes
2008	SiteAlign [20]	Ligand	Alignment of polyhedron fingerprints	Normalized distances of fingerprints	Proteases, kinases, estrogen receptors, GPCRs
2008	SOIPPA [114]	Ligand	Clique detection in graphs of atoms	Composite weighted by frequencies, PSSM, distances	Cofactor sites, SCOP classes
2009	SMAP [33]	Ligand	Clique detection in graphs of atoms	Gaussian densities from distances, angles of normal vectors, BLOSSUM weights	Cofactor sites
2010	BSSF [25]	PASS [64]	Comparison of fingerprints of binned distances and properties	Canberra distances of fingerprints	Diverse, synthetic data, SCOP classes
2010	Feldman et al. [30]	Ligand	Match of subsets of Cα atoms	Probabilistic score from distances between matches	Diverse, kinases
2010	FuzCav [24]	Ligand	Fingerprints of triplets of atom features	Maximal proportion of matches	Diverse, functional groups, 8 difficult cases
2010	Milletti et al. [115]	Ligand	Comparison of 3 concentric spheres fingerprints encoding neighborhood for each point, solving linear assignment	Composite of fingerprint distances and RMSD	ATP sites, kinases
2010	P.A.R.I.S (sup-CK) [116]	Ligand	Initial alignment optimized by gradient ascent to maximize a Gaussian kernel	Gaussian kernel	Cofactor sites
2010	ProBiS [31]	Ligand	Maximum clique detection in graphs of surface atoms	Count of Matches, RMSD, angle between vectors	Cofactor/metal sites, protein–protein interfaces, protein–DNA complexes
2011	PocketAlign [117]	Ligand	Initial pairs from sorted lists of atom distances, then extend	Count of matches, RMSD	Cofactor sites, SCOP classes
2011	PocketFEATURE [118]	Ligand	Comparison of 7 concentric spheres fingerprints encoding neighborhood for each microenvironment	Normalized Tanimoto similarity of fingerprints	Kinases
2012	KRIPO [21]	Ligand	Fingerprints of triplets of pharmacophore	Modified Tanimoto of fingerprints	Diverse, fragments subpockets, search of bioisosteric substructures
2012	Patch-Surfer [119]	Ligand LIGSITE [12]	Comparison of 3D Zernike of surface patches solving a weighted bipartite matching	Composite of surface match distances and size differences	Cofactor sites
2012	Shaper [47]	VolSite [47]	Comparison of cloud of points by Gaussian shapes matching	Tanimoto, Tversky of matches	Diverse, GPCRs, proteases
2012	TIPSA [120]	Ligand	Match of quadruplets of points, iterative refinement by Hungarian algorithm	Tanimoto of matches, overlap of volume, normalized RMSD	Cofactor sites
2013	Apoc [28]	Ligand CAVITATOR [28], LIGSITE [12]	Seed alignment by comparing secondary structures, optimized by solving linear assignment problem	Composite of vector orientation, distance, properties	Diverse, similar ligand recognition sites
2013	TrixP [121]	DoGSite [122]	Search for common shape and triplets of points by bitmap indexing	Composite of matches count, angle between vectors, mismatches penalty	Diverse, 8 difficult cases, protease, estrogen receptor, HIV reverse transcriptase
2014	eMatchSite [29]	eFindSite [123]	Template-based alignment optimized by Hungarian algorithm	Machine learning score: RMSD, residue, properties	Cofactors, steroid sites
2014	RAPMAD [26]	LIGSITE [12]	Comparison of 14 pairwise distance histograms, one for each property	Jensen–Shannon divergence of histograms	Cofactor sites, proteases, diverse
2015	IsoMIF [124]	GetCleft [125]	Clique detection in graphs of interaction grid points	Tanimoto of descriptors of matched points	Cofactors, steroid sites
2016	G-LoSA [126]	Ligand	Clique detection in graphs of atoms	Feature-weighted count of matches	Diverse, Ca+ sites, similar ligands recognition sites, protein–protein interfaces
2016	SiteHopper [127]	Ligand	Comparison of surface atoms by Gaussian shapes matching	Weighted combination of shape and color Tanimoto	Diverse using binding affinities
2019	DeepDrug3D [128]	Ligand	Convolutional neural network model	Binary classification	Cofactors, steroids sites, proteases
2020	DeeplyTough [32]	Fpocket [16] Ligand	Convolutional neural network model	Binary classification	Cofactor sites, diverse and using binding affinities
2020	ProCare [129]	VolSite [47]	Match of randomly sampled quadruplets refined by iterative closest point	Tversky of matched pharmacophoric properties	Diverse, using functional annotation, fragments subpockets, search of bioisosteric structures
2021	PocketShape [130]	Ligand	Initial alignment optimized by Hungarian algorithm	Composite of matches, orientation of residues	Diverse SCOP classes, kinases
2021	Site2Vec [131]	Ligand	Random forest model on autoencoder-generated descriptors	Binary classification	Cofactors, steroid sites, diverse