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An in silico approach for the discovery of CDK5/p25 interaction inhibitors
Author(s) -
Zhang Bing,
Corbel Caroline,
Guéritte Françoise,
Couturier Cyril,
Bach Stéphane,
Tan Vincent B. C.
Publication year - 2011
Publication title -
biotechnology journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.144
H-Index - 84
eISSN - 1860-7314
pISSN - 1860-6768
DOI - 10.1002/biot.201100139
Subject(s) - cyclin dependent kinase , virtual screening , in silico , small molecule , protein–protein interaction , kinase , computational biology , cyclin dependent kinase 5 , plasma protein binding , chemistry , binding site , activator (genetics) , microbiology and biotechnology , biology , drug discovery , biophysics , biochemistry , protein kinase a , cyclin dependent kinase 2 , cell , cell cycle , receptor , gene
The lack of selectivity of all existing ATP competitive inhibitors for a single cyclin‐dependent kinase (CDK) has led us to redirect the structure‐based molecule design from targeting the classic ATP‐binding pocket in CDK5 toward the CDK5/p25 interface. The aim was to seek novel inhibition mechanisms to interrupt protein‐protein interactions. A combined strategy of alanine‐scanning calculations for locating binding sites, virtual screening for small molecules, molecular dynamics simulations for examining the binding stability of virtual screening hits and bio‐assays for testing the level of inhibition was set up and used to explore novel inhibitors capable of interrupting the interactions between the proteins, and consequently of inhibiting the kinase activity. Two compounds were shown to inhibit the complex formation between CDK5 and p25 through p25 binding. They could open avenues for the discovery of new types of structures that prevent interactions between CDK5 and p25 or other CDK and activator proteins, and, more importantly, provide leads in the development of selective inhibitors among CDKs. Accompanying article Corbel et al.