title: Identification of potent virtual leads and ADME prediction of isoxazolidine podophyllotoxin derivatives as topoisomerase II and tubulin inhibitors.
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 β-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-β, 8a-α configuration; (2) dioxolane in ring A; (3) free rotation of ring E; (4) α (R) or β (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) β (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.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Majdi M
authors.initials: MM
authors.lastname: Bkhaitan
authors.affiliation: Science and Technology Unit (STU), Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Agha Zeeshan
authors.initials: AZ
authors.lastname: Mirza
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Hina
authors.initials: H
authors.lastname: Shamshad
authors.affiliation: Rangel College of Pharmacy, Texas A&M University, Kingsville, Texas 78363, United States; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt. Electronic address: alyismail@pharmacy.tamhsc.edu.
authors.forename: Hamed I
authors.initials: HI
authors.lastname: Ali
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D015195:Drug Design; D051379:Mice; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D011034:Podophyllotoxin / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*; D014747:Vinblastine / Q000737:chemistry / Q000494:pharmacology
chemical_list: D010080:Oxazoles; D059005:Topoisomerase II Inhibitors; D050257:Tubulin Modulators; D014747:Vinblastine; D004250:DNA Topoisomerases, Type II; D011034:Podophyllotoxin
keywords: ADMET; Molecular docking; Podophyllotoxin; Topoisomerase; Tubulin