J Chem Inf Model - ReverseScreen3D: a structure-based ligand matching method to identify protein targets.


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Ligand promiscuity, which is now recognized as an extremely common phenomenon, is a major underlying cause of drug toxicity. We have developed a new reverse virtual screening (VS) method called ReverseScreen3D, which can be used to predict the potential protein targets of a query compound of interest. The method uses a 2D fingerprint-based method to select a ligand template from each unique binding site of each protein within a target database. The target database contains only the structurally determined bioactive conformations of known ligands. The 2D comparison is followed by a 3D structural comparison to the selected query ligand using a geometric matching method, in order to prioritize each target binding site in the database. We have evaluated the performance of the ReverseScreen2D and 3D methods using a diverse set of small molecule protein inhibitors known to have multiple targets, and have shown that they are able to provide a highly significant enrichment of true targets in the database. Furthermore, we have shown that the 3D structural comparison improves early enrichment when compared with the 2D method alone, and that the 3D method performs well even in the absence of 2D similarity to the template ligands. By carrying out further experimental screening on the prioritized list of targets, it may be possible to determine the potential targets of a new compound or determine the off-targets of an existing drug. The ReverseScreen3D method has been incorporated into a Web server, which is freely available at http://www.modelling.leeds.ac.uk/ReverseScreen3D .

Resumo Limpo

ligand promiscu now recogn extrem common phenomenon major under caus drug toxic develop new revers virtual screen vs method call reversescreend can use predict potenti protein target queri compound interest method use d fingerprintbas method select ligand templat uniqu bind site protein within target databas target databas contain structur determin bioactiv conform known ligand d comparison follow d structur comparison select queri ligand use geometr match method order priorit target bind site databas evalu perform reversescreend d method use divers set small molecul protein inhibitor known multipl target shown abl provid high signific enrich true target databas furthermor shown d structur comparison improv earli enrich compar d method alon d method perform well even absenc d similar templat ligand carri experiment screen priorit list target may possibl determin potenti target new compound determin offtarget exist drug reversescreend method incorpor web server freeli avail httpwwwmodellingleedsacukreversescreend

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