Effective tailor-made force field parameterization of the several Zn coordination environments in the puzzling FTase enzyme: opening the door to the full understanding of its elusive catalytic mechanism

• Tipo: Outra Publicação em Revista Científica Internacional
• Data: 2007

Autores

Sergio Filipe Sousa (Autor) Outra; Pedro Alexandrino Fernandes (Autor) FCUP; Maria Joao Ramos (Autor) FCUP

Revista

Título: Theoretical Chemistry Accounts

Vol. 117

Páginas: 171-181

ISSN: 1432-881X

Editora: Springer Nature

Indexação

ISI Web of Knowledge - 25 Citações

Scopus - 27 Citações

Classificação Científica

FOS: Ciências exactas e naturais > Química

Outras Informações

ID Authenticus: P-004-EQ7

DOI: 10.1007/s00214-006-0170-9

Abstract (EN): Protein farnesyltransferase (FTase) is very promising anticancer drug target, with several drugs in advanced stages of clinical testing. However, in spite of the thrilling achievements in the development of farnesyltransferase inhibitors (FTIs) over the past few years, the farnesylation mechanism remains, to some degree, a mystery. This work reports the determination and validation of three sets of molecular mechanical parameters specifically tailored to accurately account for the very specific nature of the several Zn coordination spheres formed during the unclear catalytic pathway of this puzzling metalloenzyme, and built on the top of recent experimental and theoretical results that have dramatically changed the way how the farnesylation mechanism is perceived. Extensive validation studies with 14 FTase crystallographic structures, EXAFS data, DFT, and QM/MM theoretical calculations are presented.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 11