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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Anti-HIV Agents / chemical synthesis*
-
Anti-HIV Agents / chemistry
-
Anti-HIV Agents / metabolism
-
Anti-HIV Agents / pharmacology*
-
Azepines
-
Computer Simulation
-
HIV Protease / metabolism
-
HIV Protease Inhibitors / chemical synthesis*
-
HIV Protease Inhibitors / chemistry
-
HIV Protease Inhibitors / metabolism
-
HIV Protease Inhibitors / pharmacology*
-
HIV-1 / drug effects
-
HIV-1 / enzymology*
-
Hydrogen Bonding
-
Magnetic Resonance Spectroscopy
-
Mannitol / analogs & derivatives*
-
Mannitol / metabolism
-
Mannitol / pharmacology
-
Molecular Structure
-
Protein Binding
-
Sulfonamides / chemical synthesis
-
Sulfonamides / chemistry
-
Sulfonamides / metabolism
-
Sulfonamides / pharmacology
-
Urea / analogs & derivatives
-
Urea / metabolism
-
Urea / pharmacology
Substances
-
Anti-HIV Agents
-
Azepines
-
HIV Protease Inhibitors
-
Sulfonamides
-
Mannitol
-
Urea
-
HIV Protease
-
DMP 323