Computational fragment-based drug design on a mitotic kinesin
Inhibition of the mitotic spindle formation could be an interesting target for cancer therapeutics. Scientists at MEDIT recently published results of a exploratory computational fragment-based approach on an allosteric binding pocket of the Eg5 mitotic kinesin...
During cellular metaphase, a stage in eukaryotic cell mitosis, the mitotic spindle maintains a constant shape and size as their principal constituent, microtubules, are continuously polymerized, depolymerized and transported towards the two spindle poles. Kinesin motor proteins are involved in the mitotic spindle assembly, in addition to other cellular processes such as intracellular vesicle transport, chromosome segregation, cell division and motility. The role of Kinesin is discussed in this wikipedia article.
Inhibition of mitotic spindle formation is an interesting target in cancer therapeutics. The anti-mitotic agents to date cause serious side-effects, such as neurotoxicity, and the development of drug resistance restricts their application.
A different approach to inhibit the mitotic spindle formation is to inhibit the mitotic motors that interact with microtubules. Eg5 is exclusively involved in the formation and function of the mitotic spindle, driving a relative sliding of microtubules in the mitotic spindle. Inhibition of this results in cell cycle arrest and apoptosis, without interfering with other microtubule-dependent processes. Several small molecules are known to inhibit human Eg5 by binding to the catalytic motor domain. These observations imply the utility of Eg5 as an anticancer drug target.
The Eg5 allosteric binding site surface (Grey: hydrophobic, Blue: hydrophilic) showing co-crystallized monastrol (green) and mon-97 (blue) ligands, as superimposed with MED-SuMo.
My colleagues and I at MEDIT, recently developed a fragment-based drug design protocol. Based on that protocol, the aim of the work presented here was to populate the hydrophobic pocket of the Eg5 allosteric binding site, hopefully to design potential inhibitor molecules.
In the earlier work, we defined a new structural entity known as the MED-Portion. This represents ligand molecules, or substituent fragments, annotated with fragmentation anchors and interaction sites from the protein environment.
MED-Portions retrieved from known protein structures with MED-SuMo were hybridised using the MED-Hybridise and 3D substructure filtering rules to discover novel molecules having similar binding mode to the known inhibitors. Of these potential ligands, we found those that are present in publicly available chemical libraries, such as the PubChem database. We also validated the protocols through a process of recreating the structures of known inhibitors.
For more information see:
- Ksenia Oguievetskaia, Laetitia Martin-Chanas, Artem Vorotyntsev, Olivia Doppelt-Azeroual, Xavier Brotel, Stewart A. Adcock, Alexandre G. de Brevern, Francois Delfaud and Fabrice Moriaud, "Computational fragment-based drug design to explore the hydrophobic sub-pocket of the mitotic kinesin Eg5 allosteric binding site", Journal of Computer-Aided Molecular Design, 2009 June 17. Epub ahead of print (I'll update this as soon as the paper is in print)
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