title: 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.
abstract: 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.
authors.affiliation: REQUIMTE, Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal.
authors.forename: Alexandra T P
authors.initials: AT
authors.lastname: Carvalho
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Fernandes
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ramos
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D003854:Deoxyribonucleotides / Q000378:metabolism*; D024921:Drug Resistance, Multiple, Viral / Q000187:drug effects* / Q000235:genetics; D006678:HIV / Q000187:drug effects* / Q000502:physiology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006801:Humans; D008968:Molecular Conformation; D009705:Nucleosides / Q000494:pharmacology*; D017354:Point Mutation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018119:Stavudine / Q000378:metabolism / Q000031:analogs & derivatives; D013942:Thymine Nucleotides / Q000378:metabolism; D016047:Zalcitabine / Q000378:metabolism
chemical_list: D003854:Deoxyribonucleotides; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides; C053197:stavudine triphosphate; D016047:Zalcitabine; D018119:Stavudine; D054303:HIV Reverse Transcriptase