title: Cyclic HIV-1 protease inhibitors derived from mannitol: synthesis, inhibitory potencies, and computational predictions of binding affinities.
abstract: Ten C2-symmetric cyclic urea and sulfamide derivatives have been synthesized from L-mannonic gamma-lactone and D-mannitol. The results of experimental measurement of their inhibitory potencies against HIV-1 protease were compared to calculated free energies of binding derived from molecular dynamics (MD) simulations. The compounds were selected, firstly, to enable elucidation of the role of stereochemistry for binding affinity (1a-d) and, secondly, to allow evaluation of the effects of variation in the link to the P1 and P1' phenyl groups on affinity (1a and 2-5). Thirdly, compounds with hydrogen bond-accepting or-donating groups attached to the phenyl groups in the P2 and P2' side chains (6 and 7) were selected. Binding free energies were estimated by a linear response method, whose predictive power for estimating binding affinities from MD simulations was demonstrated.
authors.affiliation: Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, Uppsala University, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Hultén
authors.forename: N M
authors.initials: NM
authors.lastname: Bonham
authors.forename: U
authors.initials: U
authors.lastname: Nillroth
authors.forename: T
authors.initials: T
authors.lastname: Hansson
authors.forename: G
authors.initials: G
authors.lastname: Zuccarello
authors.forename: A
authors.initials: A
authors.lastname: Bouzide
authors.forename: J
authors.initials: J
authors.lastname: Aqvist
authors.forename: B
authors.initials: B
authors.lastname: Classon
authors.forename: U H
authors.initials: UH
authors.lastname: Danielson
authors.forename: A
authors.initials: A
authors.lastname: Karlén
authors.forename: I
authors.initials: I
authors.lastname: Kvarnström
authors.forename: B
authors.initials: B
authors.lastname: Samuelsson
authors.forename: A
authors.initials: A
authors.lastname: Hallberg
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001381:Azepines; D003198:Computer Simulation; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008353:Mannitol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015394:Molecular Structure; D011485:Protein Binding; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D001381:Azepines; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D008353:Mannitol; D014508:Urea; D016333:HIV Protease; C085816:DMP 323