Sequence-Based Design and Discovery of Peptide Inhibitors of HIV-1 Integrase:  Insight into the Binding Mode of the Enzyme

2006 ◽  
Vol 49 (15) ◽  
pp. 4477-4486 ◽  
Author(s):  
Hui-Yuan Li ◽  
Zahrah Zawahir ◽  
Lai-Dong Song ◽  
Ya-Qiu Long ◽  
Nouri Neamati
Keyword(s):  
Binding Mode ◽  
Peptide Inhibitors ◽  
Insight Into ◽  
Hiv 1

Insight into the Inhibitory Mechanism and Binding Mode Between D77 and HIV-1 Integrase by Molecular Modeling Methods

2011 ◽  
Vol 29 (2) ◽  
pp. 311-323 ◽  
Author(s):  
Ping Li ◽  
Jian Jun Tan ◽  
Ming Liu ◽  
Xiao Yi Zhang ◽  
Wei Zu Chen ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Binding Mode ◽  
Inhibitory Mechanism ◽  
Modeling Methods ◽  
Insight Into ◽  
Hiv 1

Insight into the Binding Mode between HIV-1 Integrase and Pyrimidone Analogue Inhibitors with MD Simulation and 3D-QSAR

2013 ◽  
Vol 9 (3) ◽  
pp. 420-433 ◽  
Author(s):  
Songyao Ma ◽  
Wei Ye ◽  
Dingjue Ji ◽  
Hai-Feng Chen
Keyword(s):  
Md Simulation ◽  
3D Qsar ◽  
Binding Mode ◽  
Insight Into ◽  
Hiv 1

Induced-Fit Docking Approach Provides Insight into the Binding Mode and Mechanism of Action of HIV-1 Integrase Inhibitors

ChemMedChem ◽  
2009 ◽  
Vol 4 (9) ◽  
pp. 1446-1456 ◽  
Author(s):  
Maria Letizia Barreca ◽  
Nunzio Iraci ◽  
Laura De Luca ◽  
Alba Chimirri
Keyword(s):  
Mechanism Of Action ◽  
Binding Mode ◽  
Integrase Inhibitors ◽  
Induced Fit Docking ◽  
Induced Fit ◽  
Docking Approach ◽  
Insight Into ◽  
Hiv 1

DOCKING OF RALTEGRAVIR TO HIV-1 INTEGRASE STRUCTURE ENSEMBLE

2010 ◽  
Vol 09 (06) ◽  
pp. 1053-1063 ◽  
Author(s):  
CAIYI WEI ◽  
ZEYU LIU ◽  
DAWEI ZHANG ◽  
YE MEI
Keyword(s):  
Molecular Docking ◽  
Binding Mode ◽  
Docking Studies ◽  
Water Molecules ◽  
Intermediate Water ◽  
Receptor Interactions ◽  
Complex Scheme ◽  
Insight Into ◽  
Structure Ensemble ◽  
Hiv 1

Docking of the drug raltegravir to HIV-1 integrase (IN) was performed based on the established Relaxed Complex Scheme (RCS) method which accounts for the flexibility of both receptor and ligand in molecular docking. Two representative butterfly-like structures of raltegravir were identified and both of them mimicked the binding mode of 5CITEP with similar ligand-receptor interactions. Furthermore, the results that raltegravir interacted with magnesium by intermediate water molecules indicate the importance of water molecules at the binding site which has always been ignored in the docking studies of IN inhibitors. Taking these water molecules into consideration gives more insight into the design and development of the second generation IN inhibitors.

3D-QSAR Studies of S-DABO Derivatives as Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

2019 ◽  
Vol 16 (8) ◽  
pp. 868-881
Author(s):  
Yueping Wang ◽  
Jie Chang ◽  
Jiangyuan Wang ◽  
Peng Zhong ◽  
Yufang Zhang ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Three Dimensional ◽  
Predictive Ability ◽  
3D Qsar ◽  
Binding Mode ◽  
Quantitative Structure Activity Relationship ◽  
Field Analysis ◽  
Reverse Transcriptase Inhibitors ◽  
Qsar Studies ◽  
Hiv 1

Background: S-dihydro-alkyloxy-benzyl-oxopyrimidines (S-DABOs) as non-nucleoside reverse transcriptase inhibitors have received considerable attention during the last decade due to their high potency against HIV-1. Methods: In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) of a series of 38 S-DABO analogues developed in our lab was studied using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The Docking/MMFF94s computational protocol based on the co-crystallized complex (PDB ID: 1RT2) was used to determine the most probable binding mode and to obtain reliable conformations for molecular alignment. Statistically significant CoMFA (q2=0.766 and r2=0.949) and CoMSIA (q2=0.827 and r2=0.974) models were generated using the training set of 30 compounds on the basis of hybrid docking-based and ligand-based alignment. Results: The predictive ability of CoMFA and CoMSIA models was further validated using a test set of eight compounds with predictive r2 pred values of 0.843 and 0.723, respectively. Conclusion: The information obtained from the 3D contour maps can be used in designing new SDABO derivatives with improved HIV-1 inhibitory activity.

Peptide Inhibitors of Aspartic Proteinases with Hydroxyethylene Isostere Replacement of Peptide Bond. II. Preparation of Pseudotetrapeptides Derived from Diastereoisomeric 5-Amino-2-benzyl-4-hydroxy-6-phenylhexanoic Acids

1998 ◽  
Vol 63 (4) ◽  
pp. 541-548 ◽  
Author(s):  
Jaroslav Litera ◽  
Jan Weber ◽  
Ivana Křížová ◽  
Iva Pichová ◽  
Jan Konvalinka ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Peptide Bond ◽  
Peptide Inhibitors ◽  
Aspartic Proteinases ◽  
Hiv 1

Twelve pseudotetrapeptides, Boc-NHCH(CH2Ph)CH(OH)CH2CH(CH2Ph) CO-Xaa-Phe-NH2 9-11, were prepared by [(benzotriazol-1-yl)oxy]tris(dimethylamino)phosphonium hexafluorophosphate-mediated couplings of diastereoisomeric O-silylated (2R or 2S,4R or 4S,5S)-2-benzyl-5-(tert-butoxycarbonyl)amino-4-hydroxy-6-phenylhexanoic acids 1 with dipeptides H-Xaa-Phe-NH2 (Xaa = Gln, Glu(OBzl) or Ile) 3-5, followed by O-deprotection. Pseudotetrapeptides 9-11 were tested for inhibition of aspartic proteinases secreted by Candida albicans and C. tropicalis. The level of inhibition of both yeast proteinases was very low, contrasting with the nanomolar IC50 values obtained for inhibition of HIV-1 proteinase.

scholarly journals Insight into the HIV-1 Vif SOCS-box–ElonginBC interaction

Open Biology ◽  
2013 ◽  
Vol 3 (11) ◽  
pp. 130100 ◽  
Author(s):  
Zhisheng Lu ◽  
Julien R. C. Bergeron ◽  
R. Andrew Atkinson ◽  
Torsten Schaller ◽  
Dennis A. Veselkov ◽  
...  
Keyword(s):  
Solution Structure ◽  
Hydrophobic Interactions ◽  
Dynamic Information ◽  
Ubiquitin Ligase Complex ◽  
Biophysical Studies ◽  
Viral Infectivity Factor ◽  
Β Sheet ◽  
Socs Box ◽  
Insight Into ◽  
Hiv 1

The HIV-1 viral infectivity factor (Vif) neutralizes cell-encoded antiviral APOBEC3 proteins by recruiting a cellular ElonginB (EloB)/ElonginC (EloC)/Cullin5-containing ubiquitin ligase complex, resulting in APOBEC3 ubiquitination and proteolysis. The suppressors-of-cytokine-signalling-like domain (SOCS-box) of HIV-1 Vif is essential for E3 ligase engagement, and contains a BC box as well as an unusual proline-rich motif. Here, we report the NMR solution structure of the Vif SOCS–ElonginBC (EloBC) complex. In contrast to SOCS-boxes described in other proteins, the HIV-1 Vif SOCS-box contains only one α-helical domain followed by a β-sheet fold. The SOCS-box of Vif binds primarily to EloC by hydrophobic interactions. The functionally essential proline-rich motif mediates a direct but weak interaction with residues 101–104 of EloB, inducing a conformational change from an unstructured state to a structured state. The structure of the complex and biophysical studies provide detailed insight into the function of Vif's proline-rich motif and reveal novel dynamic information on the Vif–EloBC interaction.

scholarly journals Specificity of the HIV-1 Protease on Substrates Representing the Cleavage Site in the Proximal Zinc-Finger of HIV-1 Nucleocapsid Protein

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1092
Author(s):  
János András Mótyán ◽  
Márió Miczi ◽  
Stephen Oroszlan ◽  
József Tőzsér
Keyword(s):  
Amino Acid ◽  
Zinc Finger ◽  
Cleavage Site ◽  
Potential Role ◽  
Binding Mode ◽  
Interaction Energies ◽  
Vitro Assay ◽  
Hiv 1

To explore the sequence context-dependent nature of the human immunodeficiency virus type 1 (HIV-1) protease’s specificity and to provide a rationale for viral mutagenesis to study the potential role of the nucleocapsid (NC) processing in HIV-1 replication, synthetic oligopeptide substrates representing the wild-type and modified versions of the proximal cleavage site of HIV-1 NC were assayed as substrates of the HIV-1 protease (PR). The S1′ substrate binding site of HIV-1 PR was studied by an in vitro assay using KIVKCF↓NCGK decapeptides having amino acid substitutions of N17 residue of the cleavage site of the first zinc-finger domain, and in silico calculations were also performed to investigate amino acid preferences of S1′ site. Second site substitutions have also been designed to produce “revertant” substrates and convert a non-hydrolysable sequence (having glycine in place of N17) to a substrate. The specificity constants obtained for peptides containing non-charged P1′ substitutions correlated well with the residue volume, while the correlation with the calculated interaction energies showed the importance of hydrophobicity: interaction energies with polar residues were related to substantially lower specificity constants. Cleavable “revertants” showed one residue shift of cleavage position due to an alternative productive binding mode, and surprisingly, a double cleavage of a substrate was also observed. The results revealed the importance of alternative binding possibilities of substrates into the HIV-1 PR. The introduction of the “revertant” mutations into infectious virus clones may provide further insights into the potential role of NC processing in the early phase of the viral life-cycle.

Peptide inhibitors of HIV-1 integrase: From mechanistic studies to improved lead compounds

2009 ◽  
Vol 17 (22) ◽  
pp. 7635-7642 ◽  
Author(s):  
Michal Maes ◽  
Aviad Levin ◽  
Zvi Hayouka ◽  
Deborah E. Shalev ◽  
Abraham Loyter ◽  
...  
Keyword(s):  
Peptide Inhibitors ◽  
Mechanistic Studies ◽  
Lead Compounds ◽  
Hiv 1

scholarly journals Crystal Structure of the Streptomyces coelicolor Sortase E1 Transpeptidase Provides Insight into the Binding Mode of the Novel Class E Sorting Signal

PLoS ONE ◽  
2016 ◽  
Vol 11 (12) ◽  
pp. e0167763 ◽  
Author(s):  
Michele D. Kattke ◽  
Albert H. Chan ◽  
Andrew Duong ◽  
Danielle L. Sexton ◽  
Michael R. Sawaya ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Streptomyces Coelicolor ◽  
Binding Mode ◽  
The Novel ◽  
Sorting Signal ◽  
Insight Into ◽  
Class E
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