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Molecules 2014, 19(6), 7415-7428; doi:10.3390/molecules19067415

Drug-Induced Conformational Population Shifts in Topoisomerase-DNA Ternary Complexes

1
Division of Mechanics, Research Center for Applied Sciences, Academia Sinica, 128 Academia Rd., Sec. 2, Nankang, Taipei 115, Taiwan
2
Institute of Biomedical Sciences, Academia Sinica, 128 Academia Rd., Sec. 2, Nankang, Taipei 115, Taiwan
3
School of Pharmacy, National Taiwan University, 1 Jen-Ai Rd., Sec. 2, Taipei 10051, Taiwan
*
Author to whom correspondence should be addressed.
Received: 7 March 2014 / Revised: 26 May 2014 / Accepted: 29 May 2014 / Published: 5 June 2014
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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Abstract

Type II topoisomerases (TOP2) are enzymes that resolve the topological problems during DNA replication and transcription by transiently cleaving both strands and forming a cleavage complex with the DNA. Several prominent anti-cancer agents inhibit TOP2 by stabilizing the cleavage complex and engendering permanent DNA breakage. To discriminate drug binding modes in TOP2-α and TOP2-β, we applied our newly developed scoring function, dubbed AutoDock4RAP, to evaluate the binding modes of VP-16, m-AMSA, and mitoxantrone to the cleavage complexes. Docking reproduced crystallographic binding mode of VP-16 in a ternary complex of TOP2-β with root-mean-square deviation of 0.65 Å. Molecular dynamics simulation of the complex confirmed the crystallographic binding mode of VP-16 and the conformation of the residue R503. Drug-related conformational changes in R503 have been observed in ternary complexes with m-AMSA and mitoxantrone. However, the R503 rotamers in these two simulations deviate from their crystallographic conformations, indicating a relaxation dynamics from the conformations determined with the drug replacement procedure. The binding mode of VP-16 in the cleavage complex of TOP2-α was determined by the conjoint use of docking and molecular dynamics simulations, which fell within a similar binding pocket of TOP2-β cleavage complex. Our findings may facilitate more efficient design efforts targeting TOP2-α specific drugs. View Full-Text
Keywords: topoisomerases II; molecular docking; molecular dynamics simulations; computer-aided drug design topoisomerases II; molecular docking; molecular dynamics simulations; computer-aided drug design
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Huang, N.-L.; Lin, J.-H. Drug-Induced Conformational Population Shifts in Topoisomerase-DNA Ternary Complexes. Molecules 2014, 19, 7415-7428.

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