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

• Type: Another Publication in an International Scientific Journal
• Date: 2007

Authors

Sergio Filipe Sousa (Author) Other; Pedro Alexandrino Fernandes (Author) FCUP; Maria Joao Ramos (Author) FCUP

Journal

Title: Theoretical Chemistry Accounts

Vol. 117

Pages: 171-181

ISSN: 1432-881X

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 25 Citations

Scopus - 27 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

Other information

Authenticus ID: 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11