Inhibitors of HIV-1 protease: a major success of structure-assisted drug design.

@article{Wlodawer1998InhibitorsOH,
  title={Inhibitors of HIV-1 protease: a major success of structure-assisted drug design.},
  author={Alexander Wlodawer and Jiř{\'i} Vondr{\'a}{\vs}ek},
  journal={Annual review of biophysics and biomolecular structure},
  year={1998},
  volume={27},
  pages={
          249-84
        }
}
Retroviral protease (PR) from the human immunodeficiency virus type 1 (HIV-1) was identified over a decade ago as a potential target for structure-based drug design. This effort was very successful. Four drugs are already approved, and others are undergoing clinical trials. The techniques utilized in this remarkable example of structure-assisted drug design included crystallography, NMR, computational studies, and advanced chemical synthesis. The development of these drugs is discussed in… 

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References

SHOWING 1-10 OF 170 REFERENCES
Crystal structures of HIV-1 protease-inhibitor complexes
TLDR
In this review, 25 available crystal structures of HIV PR complexes with inhibitors are described and Binding of peptidic inhibitors to the HIV PR active site are analyzed in view of the formation of potential hydrogen bonds and filling of hydrophobic space.
Structural mechanisms of HIV drug resistance.
TLDR
Structural analysis of inhibitor-enzyme complexes and mutational modeling studies are leading to a better understanding of how these drug-resistance mutations exert their effects at a structural level, which has implications of the design of new drugs and therapeutic strategies to combat drug resistance to AIDS.
Structure-based design of nonpeptide inhibitors specific for the human immunodeficiency virus 1 protease.
TLDR
A butyrophenone derivative that is a selective inhibitor of the human immunodeficiency virus 1 (HIV-1) protease is found by using a structure-based computer-assisted search and holds promise for the generation of nonpeptide protease inhibitors.
Molecular basis of HIV-1 protease drug resistance: structural analysis of mutant proteases complexed with cyclic urea inhibitors.
TLDR
The data suggest that variants persist in the presence of DMP323 and DMP450 because of a decrease in vdw interactions between the mutant proteases and inhibitors.
Antiviral and pharmacokinetic properties of C2 symmetric inhibitors of the human immunodeficiency virus type 1 protease
TLDR
A series of novel, symmetric inhibitors of HIV protease designed to match the C2 symmetric structure of the active site of the enzyme revealed broad-spectrum activity against both HIV types 1 and 2, including azidothymidine-resistant HIV, in a variety of transformed and primary human cell lines.
Bis tertiary amide inhibitors of the HIV-1 protease generated via protein structure-based iterative design.
TLDR
A series of potent nonpeptide inhibitors of the HIV protease have been identified and several modifications in the P1 and P1' pockets were suggested, highlighting the utility of crystallographic feedback in inhibitor design.
Structure of a non-peptide inhibitor complexed with HIV-1 protease. Developing a cycle of structure-based drug design.
A stable, non-peptide inhibitor of the protease from type 1 human immunodeficiency virus has been developed, and the stereochemistry of binding defined through crystallographic three-dimensional
The three-dimensional x-ray crystal structure of HIV-1 protease complexed with a hydroxyethylene inhibitor.
TLDR
This chapter discusses some of the efforts to develop a PR inhibitor by describing the structure of a complex between HIV-1 PR and a hydroxyethylene inhibitor.
Rational design of peptide-based HIV proteinase inhibitors.
TLDR
A series of peptide derivatives based on the transition-state mimetic concept has been designed that inhibit the proteinase from the human immunodeficiency virus, and antiviral activity was observed in the nanomolar range in three different cell systems.
...
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3
4
5
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