Homology modeling of Forkhead box protein C2: identification of potential inhibitors using ligand and structure-based virtual screening.
Mol Divers
; 27(4): 1661-1674, 2023 Aug.
Article
em En
| MEDLINE
| ID: mdl-36048303
ABSTRACT
Overexpression of Forkhead box protein C2 (FOXC2) has been associated with different types of carcinomas. FOXC2 plays an important role in the initiation and maintenance of the epithelial-mesenchymal transition (EMT) process, which is essential for the development of higher-grade tumors with an enhanced ability for metastasis. Thus, FOXC2 has become a therapeutic target for the development of anticancer drugs. MC-1-F2, the only identified experimental inhibitor of FOXC2, interacts with the full length of FOXC2. However, only the DNA-binding domain (DBD) of FOXC2 has resolved crystal structure. In this work, a three-dimensional (3D) structure of the full-length FOXC2 using homology modeling was developed and used for structure-based drug design (SBDD). The quality of this 3D model of the full-length FOXC2 was evaluated using MolProbity, ERRAT, and ProSA modules. Molecular dynamics (MD) simulation was also carried out to verify its stability. Ligand-based drug design (LBDD) was carried out to identify similar analogues for MC-1-F2 against 15 million compounds from ChEMBL and ZINC databases. 792 molecules were retrieved from this similarity search. De novo SBDD was performed against the full-length 3D structure of FOXC2 through homology modeling to identify novel inhibitors. The combination of LBDD and SBDD helped in gaining a better insight into the binding of MC-1-F2 and its analogues against the full length of the FOXC2. The binding free energy of the top hits was further investigated using MD simulations and MM/GBSA calculations to result in eight promising hits as lead compounds targeting FOXC2.
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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Simulação de Dinâmica Molecular
/
Antineoplásicos
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Idioma:
En
Revista:
Mol Divers
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos