ABSTRACT
[structure] Two water-soluble fullerene derivatives have been computer-designed and synthesized. They may exhibit interesting anti-HIV activity owing to the presence of two ammonium groups strategically located on the spheroid surface.
Subject(s)
Carbon/chemistry , Fullerenes , HIV Protease Inhibitors/chemical synthesis , Drug Design , Magnetic Resonance Spectroscopy , Models, MolecularABSTRACT
Aspartic proteases play key roles in a variety of pathologies, including acquired immunodeficiency syndrome. Peptidomimetic inhibitors can act as drugs to combat these pathologies. We have developed an integrated methodology for preparing human immunodeficiency virus (HIV)-1 aspartic protease diaminodiol inhibitors, based on a computational method that predicts the potential inhibitory activity of the designed structures in terms of calculated enzyme-inhibitor complexation energies. This is combined with a versatile synthetic strategy that couples a high degree of stereochemical control in the central diaminodiol module with complete flexibility in the choice of side chains in the core and in flanking residues. A series of 23 tetrameric, pentameric and hexameric inhibitors, with a wide range of calculated relative complexation energies (-47.2 to +117 kJ.mol-1) and predicted hydrophobicities (logPo/w = 1.8-8.4) was thus assembled from readily available amino acids and carboxylic acids. The IC50 values for these compounds ranged from 3.2 nM to 90 microM, allowing study of correlations between structure and activity, and individuation of factors other than calculated complexation energies that determine the inhibition potency. Multivariable regression analysis revealed the importance of side-chain bulkiness and rigidity at the P2, P2' positions, suggesting possible improvements for the prediction process used to select candidate structures.
Subject(s)
HIV Protease Inhibitors/chemistry , Computational Biology , Computer Simulation , Diamines/chemistry , Drug Design , HIV Protease Inhibitors/chemical synthesis , HIV-1/drug effects , HIV-1/enzymology , Models, Chemical , Models, Molecular , Peptides/chemistry , Structure-Activity Relationship , Substrate SpecificityABSTRACT
We report in this paper the design, by means of computational techniques, of new cyclic urea inhibitors of the HIV aspartic protease. The relationship between the complexation energies of the enzyme with known inhibitors and the experimentally determined log K(i) have been studied and used to predict inhibition constants for new inhibitors.
