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.
Highlights
Lysine specific demethylase-1 with its corepressor protein CoREST (LSD1/CoREST) has emerged as one of the most promising epigenetic targets in drug discovery and design [1]
Our group proposed that druggable regions beyond the amine oxidase domain (AOD) active site (Figure 1) might hold the key to developing pharmacologically relevant inhibitors by an allosteric mechanism revealed by extended molecular dynamics (MD) simulations [17,18]
Protein dynamics plays a major role in determining the molecular interactions available to molecular binding partners, including druggable hot spots
Summary
Lysine specific demethylase-1 with its corepressor protein CoREST (LSD1/CoREST) has emerged as one of the most promising epigenetic targets in drug discovery and design [1]. Our group proposed that druggable regions beyond the AOD active site (Figure 1) might hold the key to developing pharmacologically relevant inhibitors by an allosteric mechanism revealed by extended molecular dynamics (MD) simulations [17,18]. These new druggable regions could target protein-protein interactions necessary to the formation of multi-protein complexes [19,20,21,22,23,24,25] and/or prevent LSD1/CoREST from binding to the nucleosome [18,26]
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