title: Expanding the druggable space of the LSD1/CoREST epigenetic target: new potential binding regions for drug-like molecules, peptides, protein partners, and chromatin.
abstract: Lysine specific demethylase-1 (LSD1/KDM1A) in complex with its corepressor protein CoREST is a promising target for epigenetic drugs. No therapeutic that targets LSD1/CoREST, however, has been reported to date. Recently, extended molecular dynamics (MD) simulations indicated that LSD1/CoREST nanoscale clamp dynamics is regulated by substrate binding and highlighted key hinge points of this large-scale motion as well as the relevance of local residue dynamics. Prompted by the urgent need for new molecular probes and inhibitors to understand LSD1/CoREST interactions with small-molecules, peptides, protein partners, and chromatin, we undertake here a configurational ensemble approach to expand LSD1/CoREST druggability. The independent algorithms FTMap and SiteMap and our newly developed Druggable Site Visualizer (DSV) software tool were used to predict and inspect favorable binding sites. We find that the hinge points revealed by MD simulations at the SANT2/Tower interface, at the SWIRM/AOD interface, and at the AOD/Tower interface are new targets for the discovery of molecular probes to block association of LSD1/CoREST with chromatin or protein partners. A fourth region was also predicted from simulated configurational ensembles and was experimentally validated to have strong binding propensity. The observation that this prediction would be prevented when using only the X-ray structures available (including the X-ray structure bound to the same peptide) underscores the relevance of protein dynamics in protein interactions. A fifth region was highlighted corresponding to a small pocket on the AOD domain. This study sets the basis for future virtual screening campaigns targeting the five novel regions reported herein and for the design of LSD1/CoREST mutants to probe LSD1/CoREST binding with chromatin and various protein partners.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, The University of Utah, Salt Lake City, Utah, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Robertson
authors.forename: Nate C
authors.initials: NC
authors.lastname: Hurley
authors.forename: Marcello
authors.initials: M
authors.lastname: Tortorici
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ciossani
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Borrello
authors.forename: Nadeem A
authors.initials: NA
authors.lastname: Vellore
authors.forename: A
authors.initials: A
authors.lastname: Ganesan
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattevi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baron
mesh_terms: D001665:Binding Sites; D002843:Chromatin / Q000378:metabolism*; D056970:Co-Repressor Proteins; D018360:Crystallography, X-Ray; D044127:Epigenesis, Genetic; D056466:Histone Demethylases / Q000235:genetics*; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010455:Peptides / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D002843:Chromatin; D056970:Co-Repressor Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; C121019:RCOR1 protein, human; D012097:Repressor Proteins; D056466:Histone Demethylases; C495195:KDM1A protein, human