Insights on resistance to reverse transcriptase: The different patterns of interaction of the nucleoside reverse transcriptase inhibitors in the deoxyribonucleotide triphosphate binding site relative to the normal substrate

• Tipo: Artigo em Revista Científica Internacional
• Data: 2006

Autores

Alexandra T P Carvalho (Autor) Outra; Pedro A Fernandes (Autor) FCUP; Maria J Ramos (Autor) FCUP

Revista

Título: Journal of Medicinal Chemistry

Vol. 49

Páginas: 7675-7682

ISSN: 0022-2623

Editora: American Chemical Society

Indexação

ISI Web of Knowledge - 5 Citações

Scopus - 7 Citações

Classificação Científica

FOS: Ciências médicas e da saúde > Medicina básica

Outras Informações

ID Authenticus: P-004-FEJ

DOI: 10.1021/jm060698c

Abstract (EN): It is presently known that the long-term failure in the treatment of AIDS with the currently available nucleotide reverse transcriptase inhibitors (NRTIs) is related to the development of resistance by reverse transcriptase (RT) at the binding or incorporation level or both, or subsequent to the nucleotide incorporation (excision). To achieve greater insight on the differential interactions of two NRTIs that are mainly discriminated by different mechanisms, 2',3'-didehydro-2',3'-dideoxythymidine-5'-triphosphate (d4TTP, that is, phosphorylated stavudine) and 2',3'-dideoxycytidine-5'-triphosphate (ddCTP, that is, phosphorylated zalcitabine), with the primer/template (p/t) and with the N binding site of reverse transcriptase (RT) in relation to the normal substrate (dNTP), we have conducted a series of molecular dynamics (MD) simulations. We propose that the different resistance profiles arise from the different conformations adopted by the inhibitors at the N site. d4TTP adopts an ideal conformation for catalysis because it forms an ion-dipole intramolecular interaction with the beta-phosphate oxygen of the triphosphate, as does the normal substrate. In ddCTP, the lack of this essential interaction results in a different, noncatalytic conformation.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 8