An in silico mechanistic insight into HDAC8 activation facilitates the discovery of new small-molecule activators |
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| Institution: | 1. Department of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China;2. Shandong Cancer Hospital, Shandong University, Jinan, Shandong 250012, China;3. Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China;4. Department of Chemistry, New York University, New York, NY 10003, United States;5. NYU-ECNU Center for Computational Chemistry, New York University-Shanghai, Shanghai 200122, China;1. Department of Orthopedics, Heilongjiang Province Hospital, Harbin 150036, Heilongjiang Province, China;2. Department of Orthopedics, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China;3. Department of Orthopedics, Traditional Chinese Medicine Hospital of Harbin, Harbin 150000, Heilongjiang Province, China;4. Department of Orthopedics, Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China;1. BioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, Apartado 456, E-38071, La Laguna, Spain;2. Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071, Sevilla, Spain;1. Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, Maharashtra, India;2. Department of Biophysics and Human Physiology, Medical University of Warsaw, Chalubinskiego, Warsaw, Poland;3. Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Darmstadt, Germany;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, Egypt;2. Department of Pharmacology and Biochemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University in Egypt, 12311 Cairo, Egypt;3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk, Cairo, Egypt;1. Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, India;2. Department of Chemical Engineering and Biotechnology, University of Applied Science, Darmstadt, Germany;3. The Cellular Characterization and Biorepository Core Facility & Border Biomedical Research Centre & Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA;4. Department of Biophysics and Human Physiology, Medical University of Warsaw, Chalubinskiego, Warsaw, Poland;5. Institute of Hematology and Blood Transfusion, Indira Gandhi St., Warsaw, Poland;6. East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, USA;7. Department of Biochemistry and Molecular Biology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA |
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| Abstract: | Research interest in the development of histone deacetylase 8 (HDAC8) activators has substantially increased since loss-of-function HDAC8 mutations were found in patients with Cornelia de Lange syndrome (CdLS). A series of N-acetylthioureas (e.g., TM-2-51) have been identified as HDAC8-selective activators, among others; however, their activation mechanisms remain elusive. Herein, we performed molecular dynamics (MD) simulations and fragment-centric topographical mapping (FCTM) to investigate the mechanism of HDAC8 activation. Our results revealed that improper binding of the coumarin group of fluorescent substrates leads to the “flipping out” of catalytic residue Y306, which reduces the enzymatic activity of HDAC8 towards fluorescent substrates. A pocket between the coumarin group of the substrate and thed catalytic residue Y306 was filled with the activator TM-2-51, which not only enhanced binding between HDAC8 and the fluorescent substrate complex but also stabilized Y306 in a catalytically active conformation. Based on this newly proposed substrate-dependent activation mechanism, we performed structure-based virtual screening and successfully identified low-molecular-weight scaffolds as new HDAC8 activators. |
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| Keywords: | HDAC8 Activator Molecular dynamics simulation Virtual screening |
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