Exploring the non-covalent ligand-binding mechanism on immunoproteasome by enhanced Molecular Dynamics

Risultato della ricerca: Conference contribution


Selective inhibition of immunoproteasome is a valuable strategy to treat autoimmune andinflammatory diseases, and hematologic malignancies. In particular, non-covalent inhibitionis strongly desirable because it is free of the drawbacks and side effects associated withcovalent inhibition. Recently, a new series of amide derivatives with Ki values in the low/submicromolar ranges toward the β1i subunit have been identified as non-covalent inhibitors1. Weinvestigated the binding mechanism of the most potent and selective inhibitor (1) to elucidatethe steps from the ligand entrance into the binding pocket to the ligand-inducedconformational changes. We carried out a total of 400ns of MD-binding analysis, followed by200ns of plain MD. The trajectories clustering allowed identifying three representative posesevidencing new key interactions with Phe31 and Lys33 together to a flipped orientation of arepresentative pose. Further, Binding pose metadynamics (BPMD) studies have been performedto evaluate the binding affinity, comparing(1) with other four inhibitors of β1i subunit (2, 3, 4, and 5). Results are consistent withexperimental values of inhibition, confirming (1) as a lead compound of this series. Theadopted methods provided a full dynamic description of the binding events and the informationobtained could be exploited for the rational design of new and more active inhibitors
Lingua originaleEnglish
Titolo della pubblicazione ospite13th Young Medicinal Chemist Symposium - NPCF, Nuove prospettive in Chimica Farmaceutica Book of Abstracts
Numero di pagine1
Stato di pubblicazionePublished - 2021


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