Structure-based drug design of non-nucleoside inhibitors for wild-type and drug-resistant HIV reverse transcriptase.

@article{Mao2000StructurebasedDD,
  title={Structure-based drug design of non-nucleoside inhibitors for wild-type and drug-resistant HIV reverse transcriptase.},
  author={Cheney Mao and Elise A. Sudbeck and Taracad K Venkatachalam and Fatih M. Uckun},
  journal={Biochemical pharmacology},
  year={2000},
  volume={60 9},
  pages={
          1251-65
        }
}
The generation of anti-HIV agents using structure-based drug design methods has yielded a number of promising non-nucleoside inhibitors (NNIs) of HIV reverse transcriptase (RT). Recent successes in identifying potent NNIs are reviewed with an emphasis on the recent trend of utilizing a computer model of HIV RT to identify space in the NNI binding pocket that can be exploited by carefully chosen functional groups predicted to interact favorably with binding pocket residues. The NNI binding… 
Novel tight binding PETT, HEPT and DABO-based non-nucleoside inhibitors of HIV-1 reverse transcriptase
  • O. D'cruz, F. Uckun
  • Biology, Medicine
    Journal of enzyme inhibition and medicinal chemistry
  • 2006
TLDR
The chemistry and biological evaluation of highly potent novel phenethylthiazolylthiourea (PETT), 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and dihydroalkoxybenzyloxopyrimidine (DABO) derivatives targeting the hydrophobic binding pocket of HIV-1 RT are described.
The search for potent, small molecule NNRTIs: A review.
TLDR
A chronological history of NNRTI development is presented, also highlighting the need for small molecules belonging to the NN RTI class for the management of AIDS.
HIV‐1 NNRTIs: structural diversity, pharmacophore similarity, and impliations for drug design
TLDR
This review covers two decades of research and development for various NN RTI families based on their chemical scaffolds, and describes the structural similarity of NNRTIs.
Flexible docking of pyridinone derivatives into the non-nucleoside inhibitor binding site of HIV-1 reverse transcriptase.
TLDR
Docking results indicate that pyridinone analogues adopt a butterfly conformation and share the same binding mode as the crystal inhibitors in the pocket geometries of nevirapine, 1051U91, 9-Cl-TIBO, Cl-alpha-APA, efavirenz, UC-781, and S-1153.
Comparative study of non nucleoside inhibitors with HIV-1 reverse transcriptase based on 3D-QSAR and docking
  • H. Chen, X. Yao, +4 authors B. Fan
  • Chemistry, Medicine
    SAR and QSAR in environmental research
  • 2003
TLDR
Three 3D-QSAR models including two partial correlation models (one for each family of HEPT and TIBO) and a mixed model gathering two families were constructed showed better prediction ability, which could help to insight the interaction between NNRTIs and HIVRT, and to design new anti-HIV NN RTIs inhibitors.
Dawn of non-nucleoside inhibitor-based anti-HIV microbicides.
TLDR
Structural, biological and preclinical studies relevant to the clinical development of these NNRTIs as molecular virucides intended to prevent the sexual transmission of HIV-1 are focused on.
Steered molecular dynamics simulation on the binding of NNRTI to HIV-1 RT.
TLDR
The complementary steered molecular dynamics and conventional molecular dynamics simulation results strongly support the hypothesis that NNRTIs inhibit HIV-1 RT polymerization activity by enlarging the DNA-binding cleft and restricting the flexibility and mobility of the p66 thumb subdomain that are believed to be essential during DNA translocation and polymerization.
Effect of stereo and regiochemistry towards wild and multidrug resistant HIV-1 virus: viral potency of chiral PETT derivatives.
TLDR
Experimental evidence is provided that the stereochemistry and the regiochemistry of non-nucleoside inhibitors can profoundly affect their anti-HIV activity.
Theoretical studies on the molecular basis of HIV-1RT/NNRTIs interactions
TLDR
The interaction energy of the protein-inhibitor complexes was found to be essentially associated with the cluster of seven hydrophobic residues, considered to be the most frequently detected mutated amino acids during treatment by various NNRTIs and therefore, those most likely to have been selected in the population for resistance.
Effect of stereochemistry on the anti-HIV activity of chiral thiourea compounds.
TLDR
Experimental evidence is provided that the stereochemistry as well as regiochemistry of NNRTI can profoundly affect their anti-HIV activity.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 63 REFERENCES
The structure of HIV-1 reverse transcriptase complexed with 9-chloro-TIBO: lessons for inhibitor design.
TLDR
Although Cl-TIBO is chemically very different from other NNIs, it achieves remarkable spatial equivalence and shape complementarity with other NNs on binding to RT, and might enhance their binding and hence, potentially, their therapeutic efficacy.
Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance.
TLDR
H BY 097 binds to the mutant RT in a manner similar to that seen in the wild-type RT/HBY 097 complex, although there are some repositioning and conformational alterations of the inhibitor, suggesting that inhibitor flexibility can help to minimize drug resistance.
The PETT series, a new class of potent nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase
TLDR
Through an integrated effort involving synthesis and molecular modeling, compounds with nanomolar potency against HIV-1 in cell culture were developed and LY300046-HCl was identified as a potent nonnucleoside inhibitor of HIV- 1 RT possessing favorable pharmacokinetic properties.
Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance.
The locations of HIV-1 RT nucleoside and non-nucleoside inhibitor-binding sites and inhibitor-resistance mutations are analyzed in the context of the three-dimensional structure of the enzyme and
Structure of the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1.
  • S. Smerdon, J. Jäger, +5 authors T. Steitz
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1994
TLDR
The co-crystal-structure of HIV-1 RT and Nevirapine has been solved previously at 3.5-A resolution and now is partially refined against data extending to 2.9-A spacing, implying that there may be limitations on the number of resistance mutations that yield viable virus.
Rational design and synthesis of phenethyl-5-bromopyridyl thiourea derivatives as potent non-nucleoside inhibitors of HIV reverse transcriptase
Abstract A series of novel phenethylthiazolylthiourea (PETT) derivatives targeting the nonnucleoside inhibitor (NNI) binding site of HIV reverse transcriptase (RT) have been designed based on the
Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor.
  • R. Esnouf, J. Ren, +4 authors D. Stuart
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1997
TLDR
The structure of the complex between HIV-1 RT and the bis(heteroaryl)piperazine (BHAP) NNI reveals the inhibitor conformation and bound water molecules and suggests changes to U-90152, such as the addition of a 6 amino group to the pyridine ring, which may make binding more resilient to mutations in the RT.
The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection
TLDR
In vivo, various triple-drug combinations of NNRTIs with NRTIs and PIs and/or PIs have been shown to afford a durable anti-HIV activity, as reflected by both a decrease in plasma HIV-1 RNA levels and increased CD4 T-lymphocyte counts.
Novel concepts in the treatment of human immunodeficiency virus type 1 (HIV-1) infections by HIV-1-specific reverse transcriptase inhibitors.
  • J. Balzarini
  • Biology, Medicine
    Verhandelingen - Koninklijke Academie voor Geneeskunde van Belgie
  • 1995
TLDR
A molecular model of interaction of the NNRTI inhibitor TSAO with the binding pocket in the HIV-1 reverse transcriptase has been proposed, and now provide the rational basis for the development of second generation TSAO molecules that may become suppressive to mutant HIV- 1 strains.
Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors.
TLDR
It is suggested that a major determinant of increased potency in the analogues of HEPT is an improved interaction between residue Tyr181 in the protein and the 6-benzyl ring of the inhibitors which stabilizes the structure of the complex.
...
1
2
3
4
5
...