Document Detail


Optimization of non-ATP competitive CDK/cyclin groove inhibitors through REPLACE-mediated fragment assembly.
MedLine Citation:
PMID:  23323521     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A major challenge in drug discovery is to develop and improve methods for targeting protein-protein interactions. Further exemplification of the REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) strategy for generating inhibitors of protein-protein interactions demonstrated that it can be used to optimize fragment alternatives of key determinants, to combine these in an effective way, and this was achieved for compounds targeting the cyclin-dependent kinase 2 (CDK2) substrate recruitment site on the cyclin regulatory subunit. Phenylheterocyclic isosteres replacing a critical charge-charge interaction provided new structural insights for binding to the cyclin groove. In particular, these results shed light onto the key contributions of a H-bond observed in crystal structures of N-terminally capped peptides. Furthermore, the structure-activity relationship of a bis(aryl) ether C-terminal capping group mimicking dipeptide interactions was probed through ring substitutions, allowing increased complementarity with the primary hydrophobic pocket. This study further validates REPLACE as an effective strategy for converting peptidic compounds to more pharmaceutically relevant compounds.
Authors:
Shu Liu; Padmavathy Nandha Premnath; Joshua K Bolger; Tracy L Perkins; Lindsay O Kirkland; George Kontopidis; Campbell McInnes
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-02-12
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  56     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-07-11     Completed Date:  2013-07-31     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1573-82     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism*
Cyclin-Dependent Kinases / antagonists & inhibitors*,  chemistry
Dipeptides / chemical synthesis,  chemistry
Hydrophobic and Hydrophilic Interactions
Ligands
Models, Molecular
Oligopeptides / chemical synthesis,  chemistry*
Peptidomimetics / chemical synthesis,  chemistry*
Pyrazoles / chemical synthesis,  chemistry
Pyrroles / chemical synthesis,  chemistry
Structure-Activity Relationship
Triazoles / chemical synthesis,  chemistry
Grant Support
ID/Acronym/Agency:
5R01CA131368/CA/NCI NIH HHS; R01 CA131368/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Dipeptides; 0/Ligands; 0/Oligopeptides; 0/Peptidomimetics; 0/Pyrazoles; 0/Pyrroles; 0/Triazoles; 8L70Q75FXE/Adenosine Triphosphate; EC 2.7.11.22/Cyclin-Dependent Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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