A Rationale for Drug Design Provided by Co-Crystal Structure of IC261 in Complex with Tubulin.
Molecules
; 26(4)2021 Feb 10.
Article
em En
| MEDLINE
| ID: mdl-33579052
ABSTRACT
Microtubules composed of α/ß tubulin heterodimers are an essential part of the cytoskeleton of eukaryotic cells and are widely regarded as targets for cancer chemotherapy. IC261, which is discovered as an ATP-competitive inhibitor of serine/threonine-specific casein kinase 1 (CK1), has shown its inhibitory activity on microtubule polymerization in recent studies. However, the structural information of the interaction between tubulin and IC261 is still unclear. Here, we provided a high-resolution (2.85 Å) crystal structure of tubulin and IC261 complex, revealed the intermolecular interaction between tubulin and IC261, and analyzed the structure-activity relationship (SAR). Subsequently, the structure of tubulin-IC261 complex was compared with tubulin-colchicine complex to further elucidate the novelty of IC261. Furthermore, eight optimal candidate compounds of new IC261-based microtubule inhibitors were obtained through molecular docking studies. In conclusion, the co-crystal structure of tubulin-IC261 complex paves a way for the design and development of microtubule inhibitor drugs.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Floroglucinol
/
Tubulina (Proteína)
/
Desenho de Fármacos
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Caseína Quinase I
/
Indóis
/
Microtúbulos
Limite:
Animals
Idioma:
En
Revista:
Molecules
Ano de publicação:
2021
Tipo de documento:
Article