Solvent-Site Prediction for Fragment Docking and Its Implication on Fragment-Based Drug Discovery
The accuracy in the posing and scoring of low-affinity fragments is still a main challenge in fragment-based virtual screenings. The positive impact of including structural or predicted water molecules during docking on the docking performance is discussed frequently and is not conclusive so far. We...
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2025
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| _version_ | 1849927644208955392 |
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| author | Laura Almena Rodriguez (21008567) |
| author2 | Vera A. Spanke (22676216) Christian Kersten (9215) |
| author2_role | author author |
| author_facet | Laura Almena Rodriguez (21008567) Vera A. Spanke (22676216) Christian Kersten (9215) |
| author_role | author |
| dc.creator.none.fl_str_mv | Laura Almena Rodriguez (21008567) Vera A. Spanke (22676216) Christian Kersten (9215) |
| dc.date.none.fl_str_mv | 2025-11-24T18:03:48Z |
| dc.identifier.none.fl_str_mv | 10.1021/acs.jcim.5c02352.s004 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/dataset/Solvent-Site_Prediction_for_Fragment_Docking_and_Its_Implication_on_Fragment-Based_Drug_Discovery/30696272 |
| dc.rights.none.fl_str_mv | CC BY-NC 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biophysics Biochemistry Genetics Immunology Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified Information Systems not elsewhere classified vice versa </ comprehensive statistical evaluation binding sites occupied based virtual screenings based drug discovery fragment hit identification predicted water molecules multiple solvent models general positive impact docking tools turned fragment growing approaches water molecules positive impact fragment growing fragment redocking fragment docking template docking site prediction preferred combination pose prediction pharmacophore features main challenge larger ligands including structural including crystallographic implementing constraints docking tool docking performance docking fragments discussed frequently different targets corresponding lead consensus approach affinity fragments |
| dc.title.none.fl_str_mv | Solvent-Site Prediction for Fragment Docking and Its Implication on Fragment-Based Drug Discovery |
| dc.type.none.fl_str_mv | Dataset info:eu-repo/semantics/publishedVersion dataset |
| description | The accuracy in the posing and scoring of low-affinity fragments is still a main challenge in fragment-based virtual screenings. The positive impact of including structural or predicted water molecules during docking on the docking performance is discussed frequently and is not conclusive so far. We present a comprehensive statistical evaluation of the effect of including crystallographic or predicted water molecules on the docking performance of fragment redocking. Further, cross-docking fragments into binding sites occupied by larger ligands and <i>vice versa</i> were elucidated. These cross-dockings imitate realistic use cases of fragment hit identification and fragment growing or synthon-based virtual screenings, respectively. Therefore, a new benchmark data set, called Frag2Lead containing 103 fragment-protein and corresponding lead-protein complexes, was compiled. Inclusion of water molecules during docking had a general positive impact on docking performance, but the preferred combination of the docking tool and water model varied across the different targets. A consensus approach over multiple solvent models and docking tools turned out to be beneficial for both re- and cross-dockings. Implementing constraints by template docking or pharmacophore features is advantageous for pose prediction for fragment growing approaches. |
| eu_rights_str_mv | openAccess |
| id | Manara_5071f095e01ae30c44d206d675ff4709 |
| identifier_str_mv | 10.1021/acs.jcim.5c02352.s004 |
| network_acronym_str | Manara |
| network_name_str | ManaraRepo |
| oai_identifier_str | oai:figshare.com:article/30696272 |
| publishDate | 2025 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY-NC 4.0 |
| spelling | Solvent-Site Prediction for Fragment Docking and Its Implication on Fragment-Based Drug DiscoveryLaura Almena Rodriguez (21008567)Vera A. Spanke (22676216)Christian Kersten (9215)BiophysicsBiochemistryGeneticsImmunologyBiological Sciences not elsewhere classifiedChemical Sciences not elsewhere classifiedInformation Systems not elsewhere classifiedvice versa </comprehensive statistical evaluationbinding sites occupiedbased virtual screeningsbased drug discoveryfragment hit identificationpredicted water moleculesmultiple solvent modelsgeneral positive impactdocking tools turnedfragment growing approacheswater moleculespositive impactfragment growingfragment redockingfragment dockingtemplate dockingsite predictionpreferred combinationpose predictionpharmacophore featuresmain challengelarger ligandsincluding structuralincluding crystallographicimplementing constraintsdocking tooldocking performancedocking fragmentsdiscussed frequentlydifferent targetscorresponding leadconsensus approachaffinity fragmentsThe accuracy in the posing and scoring of low-affinity fragments is still a main challenge in fragment-based virtual screenings. The positive impact of including structural or predicted water molecules during docking on the docking performance is discussed frequently and is not conclusive so far. We present a comprehensive statistical evaluation of the effect of including crystallographic or predicted water molecules on the docking performance of fragment redocking. Further, cross-docking fragments into binding sites occupied by larger ligands and <i>vice versa</i> were elucidated. These cross-dockings imitate realistic use cases of fragment hit identification and fragment growing or synthon-based virtual screenings, respectively. Therefore, a new benchmark data set, called Frag2Lead containing 103 fragment-protein and corresponding lead-protein complexes, was compiled. Inclusion of water molecules during docking had a general positive impact on docking performance, but the preferred combination of the docking tool and water model varied across the different targets. A consensus approach over multiple solvent models and docking tools turned out to be beneficial for both re- and cross-dockings. Implementing constraints by template docking or pharmacophore features is advantageous for pose prediction for fragment growing approaches.2025-11-24T18:03:48ZDatasetinfo:eu-repo/semantics/publishedVersiondataset10.1021/acs.jcim.5c02352.s004https://figshare.com/articles/dataset/Solvent-Site_Prediction_for_Fragment_Docking_and_Its_Implication_on_Fragment-Based_Drug_Discovery/30696272CC BY-NC 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/306962722025-11-24T18:03:48Z |
| spellingShingle | Solvent-Site Prediction for Fragment Docking and Its Implication on Fragment-Based Drug Discovery Laura Almena Rodriguez (21008567) Biophysics Biochemistry Genetics Immunology Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified Information Systems not elsewhere classified vice versa </ comprehensive statistical evaluation binding sites occupied based virtual screenings based drug discovery fragment hit identification predicted water molecules multiple solvent models general positive impact docking tools turned fragment growing approaches water molecules positive impact fragment growing fragment redocking fragment docking template docking site prediction preferred combination pose prediction pharmacophore features main challenge larger ligands including structural including crystallographic implementing constraints docking tool docking performance docking fragments discussed frequently different targets corresponding lead consensus approach affinity fragments |
| status_str | publishedVersion |
| title | Solvent-Site Prediction for Fragment Docking and Its Implication on Fragment-Based Drug Discovery |
| title_full | Solvent-Site Prediction for Fragment Docking and Its Implication on Fragment-Based Drug Discovery |
| title_fullStr | Solvent-Site Prediction for Fragment Docking and Its Implication on Fragment-Based Drug Discovery |
| title_full_unstemmed | Solvent-Site Prediction for Fragment Docking and Its Implication on Fragment-Based Drug Discovery |
| title_short | Solvent-Site Prediction for Fragment Docking and Its Implication on Fragment-Based Drug Discovery |
| title_sort | Solvent-Site Prediction for Fragment Docking and Its Implication on Fragment-Based Drug Discovery |
| topic | Biophysics Biochemistry Genetics Immunology Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified Information Systems not elsewhere classified vice versa </ comprehensive statistical evaluation binding sites occupied based virtual screenings based drug discovery fragment hit identification predicted water molecules multiple solvent models general positive impact docking tools turned fragment growing approaches water molecules positive impact fragment growing fragment redocking fragment docking template docking site prediction preferred combination pose prediction pharmacophore features main challenge larger ligands including structural including crystallographic implementing constraints docking tool docking performance docking fragments discussed frequently different targets corresponding lead consensus approach affinity fragments |