title: Synthesis, anti-HIV activity studies, and in silico rationalization of cyclobutane-fused nucleosides.
abstract: The present work describes some recent approaches to novel 3-oxabicyclo[3.2.0]heptane-type nucleosides structurally similar to the potent anti-HIV agent stavudine (d4T). To gain knowledge at the molecular level relevant for further synthetic designs, the lack of activity of these compounds was investigated by computational approaches accounting for three main physiological requirements of anti-HIV nucleosides: their drug-likeness, their activation process, and their subsequent interaction with HIV reverse transcriptase (HIV-RT). Our results show that the inclusion of the fused cyclobutane at the 2'- and 3'-positions of the sugar portion provides drug-like compounds. Nonetheless, the presence of this cyclobutane moiety prevents binding orientations consistent with the catalytic activation for at least one of the enzymes known to activate d4T. To the best of our knowledge, this is the first study to explicitly consider the simulation of the entire activation process to rationalize anti-HIV activities.
authors.affiliation: Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Figueras
authors.forename: Rosa
authors.initials: R
authors.lastname: Miralles-Llumà
authors.forename: Ramon
authors.initials: R
authors.lastname: Flores
authors.forename: Albert
authors.initials: A
authors.lastname: Rustullet
authors.forename: Félix
authors.initials: F
authors.lastname: Busqué
authors.forename: Marta
authors.initials: M
authors.lastname: Figueredo
authors.forename: Josep
authors.initials: J
authors.lastname: Font
authors.forename: Ramon
authors.initials: R
authors.lastname: Alibés
authors.forename: Jean-Didier
authors.initials: JD
authors.lastname: Maréchal
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D003503:Cyclobutanes / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006678:HIV / Q000187:drug effects*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D003503:Cyclobutanes; D004791:Enzyme Inhibitors; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase