Aspartic protease inhibitors. An integrated approach for the design and synthesis of diaminodiol-based peptidomimetics
| Autor: | Anil C. Nair, Nikolinka Antcheva, Irena Bonin, Alessandro Tossi, Domenico Romeo, Fabio Benedetti, Giorgio Palù, Stefano Norbedo, Stanislav Miertus, Federico Dal Bello, Tibor Maliar |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Models
Molecular Peptidomimetic Stereochemistry Human immunodeficiency virus (HIV) Diamines medicine.disease_cause Biochemistry Substrate Specificity chemistry.chemical_compound Structure-Activity Relationship HIV-1 protease Aspartate protease Side chain medicine Ic50 values Peptide synthesis Computer Simulation chemistry.chemical_classification biology Computational Biology HIV Protease Inhibitors Amino acid chemistry Models Chemical Drug Design biology.protein HIV-1 Peptides |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|