Journal
BIOCHEMISTRY
Volume 52, Issue 13, Pages 2328-2336Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi400014t
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Funding
- National Institutes Health [CA-69571]
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Paclitaxel (PTX) is a microtubule-stabilizing agent that is widely used in cancer chemotherapy. This structurally complex natural product acts by binding to beta-tubulin in assembled microtubules. The 2'-hydroxyl group in the flexible side chain of PTX is an absolute requirement for activity, but its precise role in the drug-receptor interaction has not been specifically investigated. The contribution of the 2'-OH group to the affinity and tubulin-assembly efficacy of PTX has been evaluated through quantitative analysis of PTX derivatives possessing side chain deletions: 2'-deoxy-PTX, N-debenzoyl-2'-deoxy-PTX, and baccatin III. The affinity of 2'-deoicy-PTX for stabilized microtubules was more than 100-fold lower than that of PTX and only similar to 3-fold greater than the microtubule affinity of baccatin III. No microtubule binding activity was detected for the analogue N-debenzoy1-2'-deoxy-PTX. The tubulin-assembly efficacy of each ligand was consistent with the microtubule binding affinity, as was the trend in cytotoxicities. Molecular dynamics simulations revealed that the 2'-OH group of PTX can form a persistent hydrogen bond with D26 within the microtubule binding site. The absence of this interaction between 2'-deoxy-PTX and the receptor can account for the difference in binding free energy. Computational analyses also provide a possible explanation for why N-debenzoy1-2'-deoxy-PTX is inactive, in spite of the fact that it is essentially a substituted baccatin III. We propose that the hydrogen bonding interaction between the 2'-OH group and D26 is the most important stabilizing interaction that PTX forms with tubulin in the region of the C-13 side chain. We further hypothesize that the substituents at the 3'-position function to orient the 2'-OH group for a productive hydrogen bonding interaction with the protein.
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