Table 2.
List of software for analysis of ligand binding and drug design with respect to the water molecules in the binding cavity.
| Software | Testing set | Functionality | Remarks |
|---|---|---|---|
| Input – a single structure | |||
| AcquaAlta [60] | trypsin; dihydrofolate reductase; thymidine kinase; VEGFR2; glycogen phosphorylase; human phosphodiesterase; beta trypsin; holo-glyceraldehyde 3P dehydrogenase; HSP90; AmpC beta-lactamase; 2CDK2; ACE; COMT; HIV-1 protease; non-nucleoside adenosine deaminase; ACK1; coagulation factor Xa; EGFR |
generating of explicit water molecules at the ligand–protein interface; searching for water molecules interacting with generic functional groups of small organic molecules; generating water molecules bridging interactions between ligand and protein considering the hydration propensities of the involved functional groups and aromatic moieties | available on request: link |
| FLAP [73] | a set of 23 protein kinase structures | target-based pharmacophores; comparison of multiple protein targets; docking ligands into protein targets | commercial, standalone: link |
| JAWS [77] | neuraminidase; scytalone dehydratase; Major Urinary Protein 1; bovine β-lactoglobulin; cyclooxygenase-2 | determining the optimal placement of water molecules in a binding site; binding free energy estimation | implemented in a modified version of MCPRO, v. 2.1 [87] |
| SZMAP [75] | HIV-1 protease; neuraminidase; trypsin; factor Xa; scytalone dehydratase; oligopeptide-binding protein (OppA); |
computation of binding free energies and the corresponding thermodynamic components for water molecules in the binding site | commercial link |
| WaterFLAP [74] | adenosine A2A StaR receptor in complex with triazine | generating and scoring water networks for both apo and ligand-complex structures; binding path prediction; lipophilic hot-spot calculation | commercial, standalone: link |
| WaterScore[59] |
cutinase; xylose isomerase; penicillopepsin; galactose/glucose binding protein; proteinase A; rhizopus pepsin; actinidin; DNase I; cholesterol oxidase; RNAse A; thermitase; lipid binding protein; Fv fragment of mouse monoclonal antibody D1.3; dihydrofolate reductase |
determine conserved water molecule positions; scoring of protein–ligand interactions and determination of ligand binding mode with respect to bound and displaced water molecules | link(currently unavailable) |
| WATGEN[72] | 126 protein–peptide binding interface structures | identification of water sites; selection of the ‘best’ water sites for ligand docking; solvation thermodynamics; binding free energy estimation | no information available |
| WATsite[71] | three different structures of protein–ligand complexes of factor Xa | identification of water sites; free energy estimation | link(currently unavailable) |
| WRAPPA [76] | vinculin binding-site; truncated SNARE complex; potassium channel fragment; human relaxin-3; RNA complexed with Rev peptide; Kv1.3 channel blocker Tc32 |
identification of water sites, referred to as dehydrons | web server: link |
| WScore[78] | a set of 542 binding sites within 506 protein–ligand complexes, associated with 22 receptors | predicting the location of water sites; producing a detailed map of the water structure and displacement free energies; ligand docking and scoring | no information available |
| Input – MDsimulations | |||
| AQUA-DUCT [79], [80] | Solanum tuberosum epoxide hydrolase[88] | high-density water sites’ and/or co-solvent sites’ identification | standalone:link |
| AquaMMapS[85] | casein kinase 2; A2A adenosine receptor |
identification of spatial hot spots within the protein binding site | no information available |
| GIST [68] | Cucurbit[7]uril (CB7); factor Xa | high-density water sites’ identification; map of regions where the solvent interacts favourably with the surface or has unfavourable entropy | implemented in AmberTools |
| SPAM [84] | HIV-1 protease; hen egg-white lysozyme |
qualitative estimation of the thermodynamic profile of water in hydration sites; binding free energy estimation | implemented in AmberTools |
| SSTMap [81] | Caspase 3 | identification of water sites | link |
| STOW[70] |
HIV-1 protease-ligand complex; concanavalin A-carbohydrate complexes; cyclophilin A-ligand complexes |
computation of contribution of discrete ordered water molecules to the solvation thermodynamics; determine and analyse water sites | no information available |
| WATCLUST [69] | AmpC beta-lactamase | determine and analyse water sites | VMD plugin: link the direct transfer of the information to Autodock |
| Water-swap [82] | neuraminidase in complex with oseltamivir | calculation of binding free energy by water-swap reaction coordinate | part of the Siremol’s Sire application: link |
| WaterMap [67], [89] | streptavidin; Cox-2; antibody DB3; HIV-1 protease |
identification of water sites; solvation thermodynamics; entropic and enthalpic contributions to the free energy | commercial, part of the Schrödinger package: link |
| WatMD[83] |
Green Fluorescent Protein; Mannitol 2-Dehydrogenase |
identification of water sites | no information available |
*Information about currently unavailable software is in italics.