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Identification of novel inhibitors for the tyrosyl-DNA-phosphodiesterase 1 (Tdp1) mutant SCAN1 using virtual screening
Institution:1. Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 8, Lavrentiev Ave., Novosibirsk 630090, Russian Federation;2. Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russian Federation;3. N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, 9, Lavrentiev Ave., Novosibirsk 630090, Russian Federation;4. School of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand;5. School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Staffordshire ST5 5BG, United Kingdom;1. Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1–3, Moscow 119991, Russian Federation;2. EDASA Scientific, Via Stingi 37, San Salvo 66050, Italy;3. Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan;4. Dulbecco Telethon Laboratory of Prions & Amyloids, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, Trento 38123, Italy;5. A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov St. 28, Moscow, Russian Federation;1. Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, United States;2. College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, PR China;3. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China;1. KU Leuven, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Herestraat 49, 3000 Leuven, Belgium;2. Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA;3. KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000 Leuven, Belgium;1. Department of Pharmacy and Pharmaceutical Sciences, “A. Moro” University of Bari, Bari, Italy;2. Department of Pharmacy, “G. d''Annunzio” University of Chieti-Pescara, Chieti, Italy;3. Section In Silico Biology & Machine Learning, Leibniz-Institute for Food Systems Biology at the Technical University of Munich, Freising, Germany;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey;2. Department of Biochemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey;3. Department of Medical Biology, Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey;4. Cancer System Biology Laboratory (CanSyL), Graduate School of Informatics, Middle East Technical University, 06800 Ankara, Turkey
Abstract:Spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1) is a debilitating neurological disease that is caused by the mutation the Tyrosyl-DNA phosphodiesterase 1 (TDP1) DNA repair enzyme. The crucial His493 in TDP1′s binding site is replaced with an arginine amino acid residue rendering the enzyme dysfunctional. A virtual screen was performed against the homology model of SCAN1 and seventeen compounds were identified and tested in a novel SCAN1 specific biochemical assay. Six compounds showed activity with IC50 values between 3.5 and 25.1 µM. The most active ligand 5 (3.5 µM) is a dicoumarin followed by a close structural analogue 6 at 6.0 µM. A less potent series of β-carbolines (14 and 15) was found with potency in the mid-teens. According to molecular modelling an excellent fit for the active ligands into the binding pocket is predicted. To the best of our knowledge, data on inhibitors of the mutant form of TDP1 has not been reported previously. The virtual hits were also tested for wild type TDP1 activity and all six SCAN1 inhibitors are potent for the former, e.g., ligand 5 has a measured IC50 at 99 nM.In the last decade, TDP1 is considered as a promising target for adjuvant therapy against cancer in combination with Topoisomerase 1 poisons. The active ligands are mostly non-toxic to cancer cell lines A-549, T98G and MCF-7 as well as the immortalized WI-38 human fetal lung cells. Furthermore, ligands 5 and 7, show promising synergy in conjunction with topotecan, a clinically used topoisomerase 1 anticancer drug. The active ligands 5, 7, 14 and 15 have a good balance of the physicochemical properties required for oral bioavailability making the excellent candidates for further development.
Keywords:Spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1)  Tyrosyl-DNA phosphodiesterase 1 (TDP1)  Dicoumarin  Coumarin  β-carboline
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