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Interactions of ligands with macromolecules: Rational design of specific inhibitors of aspartic protease of HIV‐1
Author(s) -
Frecer Vladimir,
Miertus Stanislav
Publication year - 2002
Publication title -
macromolecular chemistry and physics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.57
H-Index - 112
eISSN - 1521-3935
pISSN - 1022-1352
DOI - 10.1002/1521-3935(200207)203:10/11<1650::aid-macp1650>3.0.co;2-e
Subject(s) - hiv 1 protease , protease , chemistry , enzyme , rational design , macromolecule , stereochemistry , protease inhibitor (pharmacology) , ritonavir , quantitative structure–activity relationship , enzyme inhibitor , drug design , combinatorial chemistry , human immunodeficiency virus (hiv) , computational chemistry , biochemistry , biology , materials science , nanotechnology , antiretroviral therapy , virology , viral load
We report here molecular modelling and design study of pseudopeptide inhibitors of the HIV‐1 aspartic protease as a therapeutic target for AIDS treatment. A QSAR model was developed for computed enzyme–inhibitor complexation Gibbs free energies and observed enzyme inhibition constants for a training set of potent HIV‐1 PR inhibitors. Three inhibitor candidates were found to bind the protease more strongly than ritonavir with binding driven also by hydrophobic forces, which enhances their potential use against drug‐resistant protease mutants.Linear regression of experimental inhibition constants (p K i = −log 10 K i , K i in [n M ]) and calculated enzyme–inhibitor relative complexation Gibbs free energies (ΔΔ G comp , in [kcal · mol −1 ]) for the training set of known potent PR inhibitors: p K i = 2.4406 − 0.0202 ΔΔ G comp , ( n = 11, r = 0.94, σ = 0.49, F = 50.36, α > 95%, K i prediction range: 0.001–3.0 n M ).