Fragment-guided approach to incorporating structural information into a CoMFA study: BACE-1 as an example

Autor(es)

Salum, Livia Barros ^[1] ; Valadares, Napoleao Fonseca ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ctr Biotecnol Mol Estrutural, Inst Fis Sao Carlos, BR-13560970 Sao Carlos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Computer-Aided Molecular Design; v. 24, n. 10, p. 803-817, OCT 2010.
• Citações Web of Science: 8

Resumo

Alzheimer's disease is an ultimately fatal neurodegenerative disease, and BACE-1 has become an attractive validated target for its therapy, with more than a hundred crystal structures deposited in the PDB. In the present study, we present a new methodology that integrates ligand-based methods with structural information derived from the receptor. 128 BACE-1 inhibitors recently disclosed by GlaxoSmithKline R\&D were selected specifically because the crystal structures of 9 of these compounds complexed to BACE-1, as well as five closely related analogs, have been made available. A new fragment-guided approach was designed to incorporate this wealth of structural information into a CoMFA study, and the methodology was systematically compared to other popular approaches, such as docking, for generating a molecular alignment. The influence of the partial charges calculation method was also analyzed. Several consistent and predictive models are reported, including one with r (2) = 0.88, q (2) = 0.69 and r (pred) (2) = 0.72. The models obtained with the new methodology performed consistently better than those obtained by other methodologies, particularly in terms of external predictive power. The visual analyses of the contour maps in the context of the enzyme drew attention to a number of possible opportunities for the development of analogs with improved potency. These results suggest that 3D-QSAR studies may benefit from the additional structural information added by the presented methodology. (AU)

• Processo FAPESP: 08/58316-5 - Estudos cineticos e funcionais das proteinas humanas da familia septina
• Beneficiário: Napoleão Fonseca Valadares
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 07/07294-9 - Planejamento racional de novos ligantes da beta-tubulina candidatos a fármacos com propriedades antitumorais
• Beneficiário: Lívia de Barros Salum
• Modalidade de apoio: Bolsas no Brasil - Doutorado