Receptor-independent 4D-QSAR analysis of a set of norstatine derived inhibitors of HIV-1 protease.
A training set of 27 norstatine derived inhibitors of HIV-1 protease, based on the 3(S)-amino-2(S)-hydroxyl-4-phenylbutanoic acid core (AHPBA), for which the -log IC(50) values were measured, was used to construct 4D-QSAR models. Five unique RI-4D-QSAR models, from two different alignments, were identified (q(2) = 0.86-0.95). These five models were used to map the atom type morphology of the lining of the inhibitor binding site at the HIV protease receptor site as well as predict the inhibition potencies of seven test set compounds for model validation. The five models, overall, predict the -log IC(50) activity values for the test set compounds in a manner consistent with their q(2) values. The models also correctly identify the hydrophobic nature of the HIV protease receptor site, and inferences are made as to further structural modifications to improve the potency of the AHPBA inhibitors of HIV protease. The finding of five unique, and nearly statistically equivalent, RI-4D-QSAR models for the training set demonstrates that there can be more than one way to fit structure-activity data even within a given QSAR methodology. This set of unique, equally good individual models is referred to as the manifold model.
Senese
Craig L
CL
Laboratory of Molecular Modeling and Design, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy-University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, USA.
Hopfinger
A J
AJ
D000614:Aminocaproates / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D010654:Phenylbutyrates / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D012680:Sensitivity and Specificity
D000614:Aminocaproates; D017320:HIV Protease Inhibitors; D010654:Phenylbutyrates; C034495:3-amino-2-hydroxy-5-methylhexanoic acid; D016333:HIV Protease