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Computational study and peptide inhibitors design for the CDK9 - cyclin T1 complex.
MedLine Citation:
PMID:  23296566     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Cyclin dependent kinase 9 (CDK9) is a protein that belongs to the cyclin-dependent kinases family, and its main role is in the regulation of the cell transcription processes. Since the increased activity of CDK9 is connected with the development of pathological processes such as tumor growth and survival and HIV-1 replication, inhibition of the CDK9 could be of particular interest for treating such diseases. The activation of CDK9 is initiated by the formation of CDK9/cyclin T1 complex, therefore disruption of its formation could be a promising strategy for the design of CDK9 inhibitors. In order to assist in the design of potential inhibitors of CDK9/cyclin T1 complex formation, a computational study of the CDK9/cyclin T1 interface was conducted. Ten peptides were designed using the information from the analysis of the complex, hot spot residues and fragment based design. The designed peptides were docked to CDK9 structures obtained by molecular dynamics simulations of CDK9/cyclin T1 complex and the CDK9 alone and their binding affinities were evaluated using molecular mechanics Poisson Boltzman surface area (MM-PBSA) method and steered molecular dynamics (SMD). Designed peptide sequences LQTLGF and ESIILQ, both derived from the surface of cyclin T1, as well as the peptide sequence PRWPE, derived from fragment based design, showed the most favorable binding properties and were selected for our further studies.
Authors:
Jelena Randjelović; Slavica Erić; Vladimir Savić
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-8
Journal Detail:
Title:  Journal of molecular modeling     Volume:  -     ISSN:  0948-5023     ISO Abbreviation:  J Mol Model     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9806569     Medline TA:  J Mol Model     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Organic Chemistry, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221, Belgrade, Serbia.
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