Dynamic-shared pharmacophore approach as tool to design new allosteric PRC2 inhibitors, targeting EED binding pocket

Stella Maria Cascioferro, Maria Rita Gulotta, Patrizia Diana, Jessica Lombino, Barbara Parrino, Daniela Carbone, Ugo Perricone, Maria Rita Gulotta, Jessica Lombino, Nedra Mekni, Giada De Simone, Maria De Rosa, Alessandro Padova

Research output: Contribution to journalArticlepeer-review

Abstract

Abstract: The Polycomb Repressive complex 2(PRC2) maintains a repressive chromatin state and silencesmany genes, acting as methylase on histone tails. Thisenzyme was found overexpressed in many types of cancer.In this work, we have set up a Computer-Aided Drug Designapproach based on the allosteric modulation of PRC2. Inorder to minimize the possible bias derived from using asingle set of coordinates within the protein-ligand complex,a dynamic workflow was developed. In details, moleculardynamic was used as tool to identify the most significantligand-protein interactions from several crystallized proteinstructures. The identified features were used for thecreation of dynamic pharmacophore models and dockinggrid constraints for the design of new PRC2 allostericmodulators. Our protocol was retrospectively validatedusing a dataset of active and inactive compounds, and theresults were compared to the classic approaches, throughROC curves and enrichment factor. Our approach suggestedsome important interaction features to be adopted forvirtual screening performance improvement
Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalMolecular Informatics
Volume40
Publication statusPublished - 2021

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Medicine
  • Drug Discovery
  • Computer Science Applications
  • Organic Chemistry

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