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

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3D-QSAR studies using the Comparative Molecular Field Analysis (CoMFA) methodology were conducted to predict the inhibition constants, Ki, 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/Ki=9.86), a 3,5-dimethoxy-benzyl cyclic urea derivate (molec60, predicted log 1/Ki=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.

Figure Stereoview of the contour plots of the CoMFA steric and electrostatic fields. The favorable (indicated by blue polyhedra) and unfavorable (represented by red polyhedra) electrostatic areas and also the favorable (shown by green polyhedra) and unfavorable (shown by yellow polyhedra) steric areas formed around the most active molecule, 6a.

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Acknowledgements

We thank Dr. Andrei Petrescu, Biochemistry Institute, Bucharest, for fruitful discussion.

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Authors and Affiliations

  1. Department of Physiology & Biophysics, University of Bucharest, Faculty of Biology, Splaiul Independentei 91-95, Bucharest, R-76201, Romania

    Speranta Avram & Maria-Luiza Flonta

  2. University of New Mexico School of Medicine, MSC 08 45601, University of New Mexico, Albuquerque, NM 87131

    Cristian Bologa

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  1. Speranta Avram
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Correspondence to Speranta Avram.

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Avram, S., Bologa, C. & Flonta, ML. Quantitative structure-activity relationship by CoMFA for cyclic urea and nonpeptide-cyclic cyanoguanidine derivatives on wild type and mutant HIV-1 protease. J Mol Model 11, 105–115 (2005). https://doi.org/10.1007/s00894-004-0226-5

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