Journal of Computer-Aided Molecular Design

, Volume 22, Issue 10, pp 737–745 | Cite as

Possible allosteric interactions of monoindazole-substituted P2 cyclic urea analogues with wild-type and mutant HIV-1 protease

  • Rajni Garg
  • Barun Bhhatarai


Our ongoing efforts to understand the difference in the binding pattern of HIV-1 protease inhibitor (HIVPI) with the wild-type and mutant HIV-1 protease (HIVPR) and to provide mechanistic insight are continued further. We report here the results of a recent quantitative structure–activity relationship (QSAR) study on monoindazole-substituted P2 analogues of cyclic urea HIVPIs. The QSAR models revealed an inverted parabolic relationship between biological activity and calculated molar refractivity (CMR). That is, biological activity first decreases with increase in CMR and at a certain minimum point (inversion point) it suddenly changes and increases with further increase in CMR. CMR is a measure of volume-dependent-polarizability and is an indication of the polar interactions between ligand and receptor. The results seem to be best rationalized by larger molecules inducing a change in a receptor unit that allows for a new mode of interaction. Similar QSAR models were also observed for the biological activity of these molecules tested against a panel of mutant viruses including mutant strains with single amino acid substitution (I84V), double amino acid substitutions (I84V/V82F), and multiple amino acid changes corresponding to mutations observed in clinical isolates of patients treated with Ritonavir®. Interestingly the inversion points for these mutant strains were found larger than for wild-type. The subtle but significant difference in the inversion point indicates change in the shape and size of the binding pocket. Earlier QSAR studies have shown that the correlation of biological activity with an inverted parabola is an indicative of the ‘allosteric interaction’ of the ligands with the receptor. This report presents a detail analysis of these observations.


HIV-1 Protease inhibitor Wild-type HIV-1 protease Mutant HIV-1 protease Allosteric interaction Monoindazole cyclic urea QSAR 



This study was supported by grant 2 R15 GM 069323-02 from NIH/NIGMS. The authors are indebted to Biobyte Corp., Claremont, CA for the use of CQSAR program.


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Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  1. 1.Chemistry and Biochemistry DepartmentCalifornia State University, San MarcosSan MarcosUSA
  2. 2.Chemistry DepartmentClarkson UniversityPotsdamUSA

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