Identification of potent virtual leads and ADME prediction of isoxazolidine podophyllotoxin derivatives as topoisomerase II and tubulin inhibitors.
J Mol Graph Model
; 73: 74-93, 2017 05.
Article
em En
| MEDLINE
| ID: mdl-28242581
ABSTRACT
Towards the design of new class of podophyllotoxin to target topoisomerase II and tubulin as substantial target in cancer therapy, a series of isoxazolidine podophyllotoxin derivatives were designed. Topoisomerase in complex with etoposide and four ß-tubulin in complex with zampanolide, taxol, vinblastine or colchicine were used as targets using GOLD5.2.2 as a docking module. The revealed key structural features of the highest fitness into tubulin domain have been explained as follows (1) trans orientation of the lactone (ring D) with 5a-ß, 8a-α configuration; (2) dioxolane in ring A; (3) free rotation of ring E; (4) α (R) or ß (S) configuration has equal fitness in position 5; (5) 4'-OMe; (6) phosphoramide linkage; (7) ethylene bridge between the phosphate and isoxazolidine ring; (8) benzyl moiety at N2-position of isoxazolidine ring; and (9) position 5 of isoxazolidine ring accommodated with 6-bromo-9H-purine, 2-amino-6H-purin-6-one, or N-(2-oxopyrimidin-4-yl) acetamide. All of these structural features are applicable for compounds to fit properly into topoisomerase II, except (1) ß (S) configuration has a higher score fitness than α (R) in position 5; (2) 4'-OH; and (3) position 5 of isoxazolidine ring accommodated better with 6-bromo-9H-purine, 2-amino-6H-purin-6-one or 7H-purin-6-amine. Computational ADMET and toxicity studies were in consensus with the docking results. Compounds holding ethylene bridge between phosphate and benzyl moiety at N2-position of isoxazolidine ring have the optimal pharmacokinetic properties and were calculated to be non-toxic. The predicted solubility profile for most of 4'-OMe containing compounds was good. This accomplished our aim in identifying promising new hits as antitumor agent with improved activity and less toxicity.
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Base de dados:
MEDLINE
Assunto principal:
Oxazóis
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Podofilotoxina
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DNA Topoisomerases Tipo II
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Moduladores de Tubulina
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Inibidores da Topoisomerase II
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article