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Título
Application of ensemble pharmacophore-based virtual screening to the discovery of novel antimitotic tubulin inhibitors
Autor(es)
Assunto
Ensemble pharmacophore
Virtual screening
Tubulin
Colchicine
Drug design
Antimitotic
Fecha de publicación
2021-08
Resumen
Tubulin is a well-validated target for herbicides, fungicides, anti-parasitic, and anti-tumor drugs. Many of the non-cancer tubulin drugs bind to its colchicine site but no colchicine-site anticancer drug is available. The colchicine site is composed of three interconnected sub-pockets that fit their ligands and modify others’ preference, making the design of molecular hybrids (that bind to more than one sub-pocket) a difficult task. Taking advantage of the more than eighty published X-ray structures of tubulin in complex with ligands bound to the colchicine site, we generated an ensemble of pharmacophore representations that flexibly sample the interactional space between the ligands and target. We searched the ZINC data- base for scaffolds able to fit several of the subpockets, such as tetrazoles, sulfonamides and diaryl-methanes, selected roughly ~8000 compounds with favorable predicted properties. A Flexi-pharma virtual screening, based on ensemble pharmacophore, was performed by two different methodologies. Combining the scaffolds that best fit the ensemble pharmacophore-representation, we designed a new
family of ligands, resulting in a novel tubulin modulator. We synthesized tetrazole 5 and tested it as a tubulin inhibitor in vitro. In good agreement with the design principles, it demonstrated micromolar activity against in vitro tubulin polymerization and nanomolar anti-proliferative effect against human epithelioid carcinoma HeLa cells through microtubule disruption, as shown by immunofluorescence confocal microscopy. The integrative methodology succedes in the design of new scaffolds for flexible pro-
teins with structural coupling between pockets, thus expanding the way in which computational methods can be used as significant tools in the drug design process.
URI
ISSN
2001-0370
DOI
10.1016/j.csbj.2021.07.039
Versión del editor
Aparece en las colecciones
- DSEAA. Artículos [11]
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2021_CompStrBiotJ_4360_ApplicationofEnsemblePharmacophoreBasedVirtualScreening_LGallego_etal