1. Atom-based enumeration: new eribulin analogues with low susceptibility to P-glycoprotein-mediated drug efflux.
- Author
-
Yu MJ, Zheng W, and Tendyke K
- Subjects
- Algorithms, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Computational Biology, Dose-Response Relationship, Drug, Drug Design, Drug Screening Assays, Antitumor, Furans chemical synthesis, Furans pharmacology, Humans, Ketones chemical synthesis, Ketones pharmacology, Molecular Conformation, Reproducibility of Results, Structure-Activity Relationship, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Antineoplastic Agents chemistry, Antineoplastic Agents metabolism, Furans chemistry, Furans metabolism, Ketones chemistry, Ketones metabolism
- Abstract
A series of eribulin analogues was evolved in silico through iterative atom-based enumeration employing a genetic algorithm-derived survival function to minimize predicted PgP-mediated drug efflux. Representatives of the virtual series were subsequently synthesized in the laboratory and tested in vitro for PgP-susceptibility. These new computer-inspired derivatives were found to exhibit high cell growth inhibitory activity and to be among the least sensitive to P-glycoprotein-mediated drug efflux in the eribulin series, thereby validating this approach to in silico molecular design., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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