Computational fragment-based drug design to explore the hydrophobic subpocket of the mitotic kinesin Eg5 allosteric binding site

Oguievetskaia, Ksénia; Martin-Chanas, Laetitia; Vorotyntsev, Artem; Doppelt-Azeroual, Olivia; Brotel, Xavier; Adcock, Stewart A.; Brevern, Alexandre G. de; Delfaud, François; Moriaud, Fabrice

doi:10.1186/1758-2946-2-s1-p29

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“…We note especially that in computational fragment-based design, the strategy of design bitopic ligands is markedly similar to computational fragment-based design. Recently, Oguievetska et al (99) successfully used computational fragment-based drug design to explore the hydrophobic sub-pocket of mitotic kinesin Eg5 allosteric binding site. Eg5 is a mitotic kinesin exclusively involved in the formation and function of the mitotic spindle that has attracted interest as an anticancer drug target.…”

Section: Bitopic Ligandsmentioning

confidence: 99%

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

Feng

et al. 2015

AAPS J

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Abstract. Allosteric modulators of G protein-coupled receptors (GPCRs), which target at allosteric sites, have significant advantages against the corresponding orthosteric compounds including higher selectivity, improved chemical tractability or physicochemical properties, and reduced risk of receptor oversensitization. Bitopic ligands of GPCRs target both orthosteric and allosteric sites. Bitopic ligands can improve binding affinity, enhance subtype selectivity, stabilize receptors, and reduce side effects. Discovering allosteric modulators or bitopic ligands for GPCRs has become an emerging research area, in which the design of allosteric modulators is a key step in the detection of bitopic ligands. Radioligand binding and functional assays ([ 35 S]GTPγS and ERK1/2 phosphorylation) are used to test the effects for potential modulators or bitopic ligands. High-throughput screening (HTS) in combination with disulfide trapping and fragment-based screening are used to aid the discovery of the allosteric modulators or bitopic ligands of GPCRs. When used alone, these methods are costly and can often result in too many potential drug targets, including false positives. Alternatively, low-cost and efficient computational approaches are useful in drug discovery of novel allosteric modulators and bitopic ligands to help refine the number of targets and reduce the false-positive rates. This review summarizes the state-of-the-art computational methods for the discovery of modulators and bitopic ligands. The challenges and opportunities for future drug discovery are also discussed.

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Section: Bitopic Ligandsmentioning

confidence: 99%

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

Feng

et al. 2015

AAPS J

View full text Add to dashboard Cite

show abstract

Computational fragment-based drug design to explore the hydrophobic subpocket of the mitotic kinesin Eg5 allosteric binding site

Cited by 1 publication

References 0 publications

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

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