HIV Protease Inhibitors: Peptidomimetic Drugs and Future Perspectives

Abdel‐Rahman, Hamdy M.; Alkaramany, Gamal S.; El-Koussi, Nawal A.; Youssef, Adel F.; Kiso, Yoshiaki

doi:10.2174/0929867023368890

Cited by 48 publications

(35 citation statements)

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“…Consistent better performances of the holographic descriptors were gained with the HIVP and NK dataset. In the case of HIVP this might be a consequence of the comparably higher average molecular weight and peptidic nature of these inhibitors [23]. Multiple occurrences of substructure elements like the amide bond are accounted for by the holographic fingerprint but not by the binary fingerprint representation.…”

Section: Resultsmentioning

confidence: 99%

Comparison of Three Holographic Fingerprint Descriptors and their Binary Counterparts

2005

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Molecular fingerprint representations were compared with respect to their ability to retrieve sets of ligands by retrospective similarity searching. Twelve different biological target classes were considered, and both "holographic" fingerprint vectors containing floating-point or integer values giving the frequency of occurrence of fragment types or atom pairs, and their "binary" representations were compared. The descriptors were substructure-based or grounded on topological and spatial pharmacophore type pairs. Enrichment factors between seven and 19 were obtained for the top-scoring two percent of the reference database, depending on the target class. Although the holographic fingerprints yielded higher enrichment factors on average, only for two target classes significant differences (> 20%) between holographic and binary fingerprint representations were observed. This result demonstrates that binary fingerprint representations can be applied to rapid similarity searching for most target classes without losing significant enrichment of actives in the virtual hit lists. A comparison of the individual molecules retrieved by holographic fingerprints and their binary representation revealed that significantly different sets of actives and "inactives" were found. The intersections of two virtual hit lists ranged from zero to approximately 90% for the set of known ligands. This result demonstrates that "binarization" of continuous molecular descriptors has a significant effect on the topology of chemical space and the resulting neighborhood behavior of chemical similarity searching.

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Section: Resultsmentioning

confidence: 99%

Comparison of Three Holographic Fingerprint Descriptors and their Binary Counterparts

2005

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“…Each monomer contains a prominent β hairpin loop, known as the “flap,” that projects over the substrate-binding cleft. These flaps are highly flexible and can undergo large localized conformational changes upon substrate and inhibitor binding [25–27]. …”

Section: Hiv-1 Proteasementioning

confidence: 99%

“…The inhibitors function by creating a hydrogen bond network with a tetra-coordinated structural water molecule that is tightly bound between the inhibitor and the flaps. Inhibition is also depended upon critical interactions between the catalytic aspartates and the inhibitor [27]. …”

Section: Hiv-1 Proteasementioning

confidence: 99%

Fragment Screening and HIV Therapeutics

Bauman

Patel

Arnold

2011

Topics in Current Chemistry

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Fragment screening has proven to be a powerful alternative to traditional methods for drug discovery. Biophysical methods, such as X-ray crystallography, NMR spectroscopy, and surface plasmon resonance, are used to screen a diverse library of small molecule compounds. Although compounds identified via this approach have relatively weak affinity, they provide a good platform for lead development and are highly efficient binders with respect to their size. Fragment screening has been utilized for a wide-range of targets, including HIV-1 proteins. Here, we review the fragment screening studies targeting HIV-1 proteins using X-ray crystallography or surface plasmon resonance. These studies have successfully detected binding of novel fragments to either previously established or new sites on HIV-1 protease and reverse transcriptase. In addition, fragment screening against HIV-1 reverse transcriptase has been used as a tool to better understand the complex nature of ligand binding to a flexible target.

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“…Hydroxyethylene (HE) is another important isostere of the aspartyl protease inhibitors and the HIV drug, Indina vir, which adopts it as a scaffold, was approved to go on the market several years ago [27] . Ghosh and co-workers have proven that compounds that incorporate substituted isopthalamides as P 2 -P 3 ligands in combination with the Leu-Ala HE dipeptide isostere can also form direct hydrogen bonds with the catalytic aspartates and display excellent potencies toward BACE-1; this group discovered the most potent compound, GRL-7234, described above [14] .…”

Section: Introductionmentioning

confidence: 99%

Discovery of potent β-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids

Zhu

Xiao

et al. 2009

Acta Pharmacol Sin

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Aim:The aim of this study was to design and synthesize a series of high activity compounds against aspartyl protease β-secretase (BACE-1) bearing hydroxyethylene (HE) framework.Methods: First, we designed the small library based on our previous work and rational analysis. Subsequently, thirteen compounds were selected and synthesized using skilled solid phase synthetic methods to explore the relationship between structure and activity. We then used molecular modeling to explain the possible binding mode. Results:Thirteen new compounds (6-18) have been designed, synthesized and bioassayed. Their structures were determined by nuclear magnetic resonance (NMR) spectra, low-and high-resolution mass spectra and optical rotation. Most compounds have shown moderate to excellent activities, and compound 10, which contains fewer amino acids and amide bonds than GRL-7234, was about 5-fold more potent than the control compound 4 discovered by Merck. The molecular modeling results have indicated the possible binding mode and explained the difference between compounds 10 and 16, providing direction for further study. Conclusion:This study yielded several high activity compounds bearing fewer amino acids and amide bonds than previous compounds, providing insight into the further development of potent BACE-1 inhibitors for the treatment of Alzheimer's disease.

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HIV Protease Inhibitors: Peptidomimetic Drugs and Future Perspectives

Cited by 48 publications

References 0 publications

Comparison of Three Holographic Fingerprint Descriptors and their Binary Counterparts

Comparison of Three Holographic Fingerprint Descriptors and their Binary Counterparts

Fragment Screening and HIV Therapeutics

Discovery of potent β-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids

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