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 Full article

Journal

Bioorganic and Medicinal Chemistry
ISSN: 0968-0896 , E-ISSN: 1464-3391

Output data

Year: 2020, Volume: 28, Number: 1, Article number : 115234, Pages count : DOI: 10.1016/j.bmc.2019.115234

Tags

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

Authors

Mamontova E.M. ^1,2 , Zakharenko A.L. ¹ , Zakharova O.D. ¹ , Dyrkheeva N.S. ¹ , Volcho K.P. ^2,3 , Reynisson J. ^4,5 , Arabshahi H.J. ⁴ , Salakhutdinov N.F. ^2,3 , Lavrik O.I. ¹

Affiliations

1	(Данные Web of science) Russian Acad Sci, Inst Chem Biol & Fundamental Med, Siberian Branch, 8 Lavrentiev Ave, Novosibirsk 630090, Russia
2	(Данные Web of science) Novosibirsk State Univ, Dept Nat Sci, Novosibirsk, Russia
3	(Данные Web of science) Russian Acad Sci, NN Vorozhtsov Novosibirsk Inst Organ Chem, Siberian Branch, 9 Lavrentiev Ave, Novosibirsk 630090, Russia
4	(Данные Web of science) Univ Auckland, Sch Chem Sci, Private Bag 92019,Victoria St West, Auckland 1142, New Zealand
5	(Данные Web of science) Keele Univ, Sch Pharm & Bioengn, Hornbeam Bldg, Keele ST5 5BG, Staffs, England

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 mu M. The most active ligand 5 (3.5 mu M) is a dicoumarin followed by a close structural analogue 6 at 6.0 mu M. A less potent series of beta-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.

Mamontova E.M. , Zakharenko A.L. , Zakharova O.D. , Dyrkheeva N.S. , Volcho K.P. , Reynisson J. , Arabshahi H.J. , Salakhutdinov N.F. , Lavrik O.I.
Identification of novel inhibitors for the tyrosyl-DNA-phosphodiesterase 1 (Tdp1) mutant SCAN1 using virtual screening

Bioorganic and Medicinal Chemistry. 2020. V.28. N1. 115234 . DOI: 10.1016/j.bmc.2019.115234 WOS Scopus РИНЦ OpenAlex

Full text from publisher

Published print:

Jan 1, 2020

Web of science:	WOS:000503435200024
Scopus:	2-s2.0-85076526763
Elibrary:	43220469
OpenAlex:	W2994355210

DB	Citing
Web of science	8
Scopus	7
Elibrary	7
OpenAlex	8