2. Academic Validation
  3. Identification of novel inhibitors for the tyrosyl-DNA-phosphodiesterase 1 (Tdp1) mutant SCAN1 using virtual screening

Identification of novel inhibitors for the tyrosyl-DNA-phosphodiesterase 1 (Tdp1) mutant SCAN1 using virtual screening

  • Bioorg Med Chem. 2020 Jan 1;28(1):115234. doi: 10.1016/j.bmc.2019.115234.
E M Mamontova 1,  A L Zakharenko 2,  O D Zakharova 2,  N S Dyrkheeva 2,  K P Volcho 3,  J Reynisson 4,  H J Arabshahi 5,  N F Salakhutdinov 3,  O I Lavrik 6
Affiliations

Affiliations

  • 1 Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 8, Lavrentiev Ave., Novosibirsk 630090, Russian Federation; Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russian Federation.
  • 2 Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 8, Lavrentiev Ave., Novosibirsk 630090, Russian Federation.
  • 3 Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russian Federation; 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; School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Staffordshire ST5 5BG, United Kingdom.
  • 5 School of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand.
  • 6 Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 8, Lavrentiev Ave., Novosibirsk 630090, Russian Federation. Electronic address: lavrik@niboch.nsc.ru.
PMID: 31831297 DOI: 10.1016/j.bmc.2019.115234
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

Coumarin; Dicoumarin; Spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1); Tyrosyl-DNA phosphodiesterase 1 (TDP1); β-carboline.

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