Ligand modifications to reduce the relative resistance of multi-drug resistant HIV-1 protease

Dewdney, Tamaria G.; Wang, Yong; Liu, Zhigang; Sharma, Shiv K.; Reiter, Samuel J.; Brunzelle, J.S.; Kovari, Iulia A.; Woster, Patrick M.; Kovari, Ladislau C.

doi:10.1016/j.bmc.2013.09.045

Cited by 1 publication

(1 citation statement)

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“…Here; we report two new flap conformations; designated twisted and tucked; in the dimers of PR20 D25N crystallized in the absence of inhibitor. Three highly drug resistant variants PR P51 ; MDR769 and PR20 were observed to have widely separated flaps in their dimer structures; suggesting a common mechanism for resistance to inhibitors [16; 21; 58]; and new inhibitors have been designed to target the wide open flaps [59]. Among the new structures reported here; PR20 D25N twist has the highest separation of the flap tips in the dimer.…”

Section: Discussionmentioning

confidence: 95%

Conformational variation of an extreme drug resistant mutant of HIV protease

Shen

Chang

Agniswamy

et al. 2015

Journal of Molecular Graphics and Modelling

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Molecular mechanisms leading to high level drug resistance have been analyzed for the clinical variant of HIV-1 protease bearing 20 mutations (PR20); which has several orders of magnitude worse affinity for tested drugs. Two crystal structures of ligand-free PR20 with the D25N mutation of the catalytic aspartate (PR20D25N) revealed three dimers with different flap conformations. The diverse conformations of PR20D25N included a dimer with one flap in a unique “tucked” conformation; directed into the active site. Analysis of molecular dynamics (MD) simulations of the ligand-free PR20 and wild-type enzymes showed that the mutations in PR20 alter the correlated interactions between two monomers in the dimer. The two flaps tend to fluctuate more independently in PR20 than in the wild type enzyme. Combining the results of structural analysis by X-ray crystallography and MD simulations; unusual flap conformations and weakly correlated inter-subunit motions may contribute to the high level resistance of PR20.

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