scholarly journals High Specificity in Protein Recognition by Hydrogen-Bond-Surrogate α-Helices: Selective Inhibition of the p53/MDM2 Complex

ChemBioChem ◽  
2010 ◽  
Vol 11 (15) ◽  
pp. 2104-2107 ◽  
Author(s):  
Laura K. Henchey ◽  
Jason R. Porter ◽  
Indraneel Ghosh ◽  
Paramjit S. Arora
Keyword(s):  
Hydrogen Bond ◽  
High Specificity ◽  
Selective Inhibition ◽  
Protein Recognition ◽  
Hydrogen Bond Surrogate

scholarly journals Biological effects of simple changes in functionality on rhodium metalloinsertors

2013 ◽  
Vol 371 (1995) ◽  
pp. 20120117 ◽  
Author(s):  
Alyson G. Weidmann ◽  
Alexis C. Komor ◽  
Jacqueline K. Barton
Keyword(s):  
Cellular Proliferation ◽  
Biological Effects ◽  
High Specificity ◽  
Selective Inhibition ◽  
Binding Affinities ◽  
Structural Modifications ◽  
Dna Mismatch ◽  
Dna Mismatches ◽  
Sensitive Structure ◽  
Function Relationship

DNA mismatch repair (MMR) is crucial to ensuring the fidelity of the genome. The inability to correct single base mismatches leads to elevated mutation rates and carcinogenesis. Using metalloinsertors–bulky metal complexes that bind with high specificity to mismatched sites in the DNA duplex–our laboratory has adopted a new chemotherapeutic strategy through the selective targeting of MMR-deficient cells, that is, those that have a propensity for cancerous transformation. Rhodium metalloinsertors display inhibitory effects selectively in cells that are deficient in the MMR machinery, consistent with this strategy. However, a highly sensitive structure–function relationship is emerging with the development of new complexes that highlights the importance of subcellular localization. We have found that small structural modifications, for example a hydroxyl versus a methyl functional group, can yield profound differences in biological function. Despite similar binding affinities and selectivities for DNA mismatches, only one metalloinsertor shows selective inhibition of cellular proliferation in MMR-deficient versus -proficient cells. Studies of whole-cell, nuclear and mitochondrial uptake reveal that this selectivity depends upon targeting DNA mismatches in the cell nucleus.

scholarly journals Reversible α-helix formation controlled by a hydrogen bond surrogate

Tetrahedron ◽  
2012 ◽  
Vol 68 (23) ◽  
pp. 4434-4437 ◽  
Author(s):  
Stephen E. Miller ◽  
Neville R. Kallenbach ◽  
Paramjit S. Arora
Keyword(s):  
Hydrogen Bond ◽  
Hydrogen Bond Surrogate ◽  
Helix Formation ◽  
Α Helix

scholarly journals Correction to Inhibition of Hypoxia Inducible Factor 1–Transcription Coactivator Interaction by a Hydrogen Bond Surrogate α-Helix

2012 ◽  
Vol 134 (18) ◽  
pp. 8000-8000 ◽  
Author(s):  
Laura K. Henchey ◽  
Swati Kushal ◽  
Ramin Dubey ◽  
Ross N. Chapman ◽  
Bogdan Z. Olenyuk ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Hydrogen Bond Surrogate ◽  
Α Helix ◽  
Transcription Coactivator

scholarly journals Dynamical Binding of Hydrogen-Bond Surrogate Derived Bak Helices to Antiapoptotic Protein Bcl-xL

2009 ◽  
Vol 113 (11) ◽  
pp. 3565-3571 ◽  
Author(s):  
Ju Bao ◽  
Xiao Y. Dong ◽  
John Z. H. Zhang ◽  
Paramjit S. Arora
Keyword(s):  
Hydrogen Bond ◽  
Antiapoptotic Protein ◽  
Hydrogen Bond Surrogate

Sub-Pharmacophore Generation of JNK3 Inhibitors

2013 ◽  
Vol 444-445 ◽  
pp. 1756-1760 ◽  
Author(s):  
Yan Ling Zhang ◽  
Yuan Ming Wang ◽  
Yan Jiang Qiao
Keyword(s):  
Hydrogen Bond ◽  
Pharmacophore Model ◽  
High Specificity ◽  
Data Bank ◽  
Chinese Herbs ◽  
Mitogen Activated Protein Kinase ◽  
Specific Class ◽  
Hydrogen Bond Donor ◽  
Hydrogen Bond Acceptor ◽  
Appraisal Index

The structure-based pharmacophore (SBP) model is consisted by the complementarity of the chemical features and space of the interaction between the ligand and receptor. The SBP models always have a high specificity which can only represent the specific class of the ligand. To simplify the models, sub-pharmacophore was then proposed in present study, and was expected to have and only have the most important or the common chemical features which play the major role in the interaction of ligand and receptor. Sub-pharmacophore should contain 4-6 features, the higher specificity with more features, and vice versa. The sub-pharmacophore was generated by the random combination of features from the structure-based models. With the MDL Drug Data Report database used as the testing database, a new metric CAI (comprehensive appraisal index), which integrated the metrics of E and A%, was defined and used to determine the best sub-pharmacophore model. C-Jun N-terminal kinase (JNKs) is one of the mitogen-activated protein kinase family, and widely involved in immune response and inflammatory response, and other pathological processes. JNK3 is mainly distributed in the brain and nervous system. In present study, twenty-five initial SBP models of JNK3 inhibitors were directly constructed from the Protein Data Bank (PDB) complexes by the LigandScout software. Then, 1018 sub-pharmacophore models were obtained from the 25 initial models. Finally, the best sub-pharmacophore was determined which was simplified from the initial model generated from the 3FI2 complex, and included four features: one hydrogen bond donor, one hydrogen bond acceptor, and two hydrophobic groups. The metrics of E, A% and CAI value of the best sub-pharmacophore model are 17.47, 31.15 and 5.44, respectively. The potential JNK3 inhibitors were then identified from Chinese herbs with the best sub-pharmacophore model, and 286 compounds were obtained.

scholarly journals Evaluation of Biologically Relevant Short α-Helices Stabilized by a Main-Chain Hydrogen-Bond Surrogate

2006 ◽  
Vol 128 (28) ◽  
pp. 9248-9256 ◽  
Author(s):  
Deyun Wang ◽  
Kang Chen ◽  
John L. Kulp ◽  
Paramjit S. Arora
Keyword(s):  
Hydrogen Bond ◽  
Main Chain ◽  
Biologically Relevant ◽  
Hydrogen Bond Surrogate
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