Abstract
Cyclin-dependent kinases (CDKs) play a key role in the cell cycle and are important anti-cancer drug targets. The natural product fascaplysin inhibits CDK4 with surprising selectivity (IC50 = 0.4 µM) compared to the close homolog CDK2 (IC50 = 500 µM). Free energy calculations of the positively charged fascaplysin and an uncharged iso-electronic derivative in the CDK2 and CDK4 inhibitor complexes indicate that the positive charge of fascaplysin is crucial for selectivity. This finding will guide further improvements in the design of fascaplysin-based selective inhibitors for CDK4.
Highlights
Cyclin dependent kinases (CDKs) are a group of protein kinases which regulate different stages of the eukaryotic cell cycle [1,2,3,4]
Before experimentally determined CDK4 structures became available, CDK4 homology models based on experimentally determined structures of CDK 2 and/or CDK6 were commonly used for computational studies such as ligand docking e.g. [34,75,76,77] and molecular dynamics simulations [78,79,80]
CDK4 homology models representing the active form still have been used in recent ligand docking studies, despite the availability of experimentally determined CDK4 structures. [41,82] To take advantage of the new Xray structures we opted for a ‘hybrid model’ strategy for studying the binding behaviour and selectivity of fascaplysin
Summary
Cyclin dependent kinases (CDKs) are a group of protein kinases which regulate different stages of the eukaryotic cell cycle [1,2,3,4]. PRb is a negative regulator of the E2F family of transcription factors [7], phosphorylation of pRb results in the release of transcription factors which activate the expression of the S-phase genes. This process enables the cell to pass through the restriction point and results in the onset of the S-phase [7,8,9]. Cell cycle regulators are frequently mutated in human cancers and due to their central role in G1 regulation CDKs offer attractive targets for therapeutic inhibition [10,11,12]. The CDK4/CyclinD1 complex as an anti-cancer drug target has been further validated in MCF-7 breast cancer cells [15]
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