Computational Studies on HIV-1 Protease Inhibitors:  Influence of Calculated Inhibitor−Enzyme Binding Affinities on the Statistical Quality of 3D-QSAR CoMFA Models

2000 ◽  
Vol 43 (23) ◽  
pp. 4446-4451 ◽  
Author(s):  
Philippa R. N. Jayatilleke ◽  
Anil C. Nair ◽  
Randy Zauhar ◽  
William J. Welsh
Keyword(s):  
Protease Inhibitors ◽  
3D Qsar ◽  
Computational Studies ◽  
Binding Affinities ◽  
Statistical Quality ◽  
Enzyme Binding ◽  
Hiv 1

scholarly journals Molecular Basis for Increased Susceptibility of Isolates with Atazanavir Resistance-Conferring Substitution I50L to Other Protease Inhibitors

2005 ◽  
Vol 49 (9) ◽  
pp. 3825-3832 ◽  
Author(s):  
Joseph Yanchunas ◽  
David R. Langley ◽  
Li Tao ◽  
Ronald E. Rose ◽  
Jacques Friborg ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Cross Resistance ◽  
Titration Calorimetry ◽  
Binding Affinities ◽  
The Novel ◽  
Immunodeficiency Virus ◽  
Effective Drugs ◽  
Hiv 1

ABSTRACT Protease inhibitors (PIs) are highly effective drugs against the human immunodeficiency virus (HIV), yet long-term therapeutic use is limited by emergence of HIV type 1 (HIV-1) protease substitutions that confer cross-resistance to multiple protease inhibitor drugs. Atazanavir is a highly potent HIV protease inhibitor with a distinct resistance profile that includes effectiveness against most HIV-1 isolates resistant to one or two PIs. The signature resistance substitution for atazanavir is I50L, and it is frequently (53%) accompanied by a compensatory A71V substitution that helps restore viability and increases atazanavir resistance levels. We measured the binding affinities of wild-type (WT) and I50L/A71V HIV-1 proteases to atazanavir and other currently approved PIs (ritonavir, lopinavir, saquinavir, nelfinavir, indinavir, and amprenavir) by isothermal titration calorimetry. Remarkably, we find that all of the PIs have 2- to 10-fold increased affinities for I50L/A71V protease, except for atazanavir. The results are also manifested by thermal stability measures of affinity for WT and I50L/A71V proteases. Additional biophysical and enzyme kinetics experiments show I50L/A71V protease is a stable enzyme with catalytic activity that is slightly reduced (34%) relative to the WT. Computational modeling reveals that the unique resistance phenotype of I50L/A71V protease likely originates from bulky tert-butyl groups at P2 and P2′ (specific to atazanavir) that sterically clash with methyl groups on residue L50. The results of this study provide a molecular understanding of the novel hypersusceptibility of atazanavir-resistant I50L/A71V-containing clinical isolates to other currently approved PIs.

Cyclic HIV-1 Protease Inhibitors Derived from Mannitol:  Synthesis, Inhibitory Potencies, and Computational Predictions of Binding Affinities

1997 ◽  
Vol 40 (6) ◽  
pp. 885-897 ◽  
Author(s):  
Johan Hultén ◽  
Nicholas M. Bonham ◽  
Ulrika Nillroth ◽  
Tomas Hansson ◽  
Guido Zuccarello ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Binding Affinities ◽  
Hiv 1 ◽  
Computational Predictions

3D-QSAR studies on chromone derivatives as HIV-1 protease inhibitors

2004 ◽  
Vol 689 (1-2) ◽  
pp. 99-106 ◽  
Author(s):  
Jiraporn Ungwitayatorn ◽  
Weerasak Samee ◽  
Jutarat Pimthon
Keyword(s):  
Protease Inhibitors ◽  
3D Qsar ◽  
Qsar Studies ◽  
Chromone Derivatives ◽  
Hiv 1

3D-QSAR, CoMFA, and CoMSIA of new phenyloxazolidinones derivatives as potent HIV-1 protease inhibitors

2012 ◽  
Vol 24 (2) ◽  
pp. 433-444 ◽  
Author(s):  
Hamid Abedi ◽  
Homeira Ebrahimzadeh ◽  
Jahan B. Ghasemi
Keyword(s):  
Protease Inhibitors ◽  
3D Qsar ◽  
Hiv 1
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