Quantitative structure-activity relationship by CoMFA for cyclic urea and nonpeptide-cyclic cyanoguanidine derivatives on wild type and mutant HIV-1 protease

3D-QSAR studies using the Comparative Molecular Field Analysis (CoMFA) methodology were conducted to predict the inhibition constants, K(i), and the inhibitor concentrations, IC90 of 127 symmetrical and unsymmetrical cyclic urea and cyclic cyanoguanidine derivatives containing different substituent...

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Bibliographic Details
Published in:Journal of molecular modeling 2005-03, Vol.11 (2), p.105-115
Main Authors: Avram, Speranta, Bologa, Cristian, Flonta, Maria-Luiza
Format: Article
Language:English
Subjects:
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Drug Evaluation, Preclinical - methods
Drug Resistance, Viral
Guanidines - chemistry
Guanidines - pharmacology
HIV Protease Inhibitors - chemistry
HIV Protease Inhibitors - pharmacology
HIV-1 - drug effects
HIV-1 - enzymology
HIV-1 - genetics
Humans
Models, Molecular
Mutation
Quantitative Structure-Activity Relationship
Urea - analogs & derivatives
Urea - chemistry
Urea - pharmacology
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Summary:3D-QSAR studies using the Comparative Molecular Field Analysis (CoMFA) methodology were conducted to predict the inhibition constants, K(i), and the inhibitor concentrations, IC90 of 127 symmetrical and unsymmetrical cyclic urea and cyclic cyanoguanidine derivatives containing different substituent groups such as: benzyl, isopropyl, 4-hydroxybenzyl, ketone, oxime, pyrazole, imidazole, triazole and having anti-HIV-1 protease activities. A significant cross-validated correlation coefficient (q2) of 0.63 and a fitted correlation coefficient r2 of 0.70 were obtained, indicating that the models can predict the anti-protease activity from poorly to highly active compounds reliably. The best predictions were obtained for: XV643 (predicted log 1/K(i) = 9.86), a 3,5-dimethoxy-benzyl cyclic urea derivate (molec60, predicted log 1/K(i) = 8.57) and a benzyl cyclic urea derivate (molec 61, predicted log 1/IC90 = 6.87). Using the CoMFA method, we also predicted the biological activity of 14 cyclic urea derivatives that inhibit the HIV-1 protease mutants V82A, V82I and V82F. The predicted biological activities of the: (i) XNO63 (inhibitory activity on the mutant HIV-1 PR V82A), (ii) SB570 (inhibiting the mutant HIV-1 PR V82I) and also (iii) XV652 (during the interaction with the mutant HIV-1 PR V82F) were in good agreement with the experimental values.
ISSN:1610-2940
0948-5023
DOI:10.1007/s00894-004-0226-5