TY - JOUR

T1 - Identification of novel inhibitors for the tyrosyl-DNA-phosphodiesterase 1 (Tdp1) mutant SCAN1 using virtual screening

AU - Mamontova, E. M.

AU - Zakharenko, A. L.

AU - Zakharova, O. D.

AU - Dyrkheeva, N. S.

AU - Volcho, K. P.

AU - Reynisson, J.

AU - Arabshahi, H. J.

AU - Salakhutdinov, N. F.

AU - Lavrik, O. I.

N1 - Funding Information: This work was supported by the Russian State-funded budget project (AAAA-A17-117020210022-4.) and grant from the Russian Foundation for Basic Research (17-04-01071). The cell lines T98G and WI-38 was obtained from the Russian Cell Culture Collection (RCCC) Institute of Cytology RAS, St. Petersburg, Russia. Publisher Copyright: © 2019 Elsevier Ltd Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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.

AB - 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.

KW - Coumarin

KW - Dicoumarin

KW - Spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1)

KW - Tyrosyl-DNA phosphodiesterase 1 (TDP1)

KW - β-carboline

KW - HUMAN-CELLS

KW - EMPIRICAL SCORING FUNCTIONS

KW - TOPOISOMERASE-I

KW - VANADATE

KW - FRAGMENTS

KW - ENHANCE

KW - DAMAGE REPAIR

KW - CAMPTOTHECIN

KW - PROTEIN-LIGAND DOCKING

KW - beta-carboline

KW - BINDING

UR - http://www.scopus.com/inward/record.url?scp=85076526763&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2019.115234

DO - 10.1016/j.bmc.2019.115234

M3 - Article

C2 - 31831297

AN - SCOPUS:85076526763

VL - 28

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 1

M1 - 115234

ER -