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Dynamic‐shared Pharmacophore Approach as Tool to Design New Allosteric PRC2 Inhibitors, Targeting EED Binding Pocket
Author(s) -
Lombino Jessica,
Gulotta Maria Rita,
De Simone Giada,
Mekni Nedra,
De Rosa Maria,
Carbone Daniela,
Parrino Barbara,
Cascioferro Stella Maria,
Diana Patrizia,
Padova Alessandro,
Perricone Ugo
Publication year - 2021
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.202000148
Subject(s) - pharmacophore , allosteric regulation , prc2 , virtual screening , computational biology , computer science , docking (animal) , workflow , histone , chemistry , histone h3 , biology , biochemistry , enzyme , gene , medicine , nursing , database
The Polycomb Repressive complex 2 (PRC2) maintains a repressive chromatin state and silences many genes, acting as methylase on histone tails. This enzyme was found overexpressed in many types of cancer. In this work, we have set up a Computer‐Aided Drug Design approach based on the allosteric modulation of PRC2. In order to minimize the possible bias derived from using a single set of coordinates within the protein‐ligand complex, a dynamic workflow was developed. In details, molecular dynamic was used as tool to identify the most significant ligand‐protein interactions from several crystallized protein structures. The identified features were used for the creation of dynamic pharmacophore models and docking grid constraints for the design of new PRC2 allosteric modulators. Our protocol was retrospectively validated using a dataset of active and inactive compounds, and the results were compared to the classic approaches, through ROC curves and enrichment factor. Our approach suggested some important interaction features to be adopted for virtual screening performance improvement.