Insight into the Inhibition of Human Choline Kinase: Homology Modeling and Molecular Dynamics Simulations

• Published in: ChemMedChem Vol. 1; no. 11; pp. 1216 - 1228
• Main Authors: Milanese, Lara, Espinosa, Antonio, Campos, Joaquín M., Gallo, Miguel A., Entrena, Antonio
• Format: Journal Article
• Language: English; German
• Published: Weinheim WILEY-VCH Verlag 13.11.2006; WILEY‐VCH Verlag
• Subjects: Amino Acid Sequence; Animals; Caenorhabditis elegans - enzymology; choline kinase; Choline Kinase - antagonists & inhibitors; Choline Kinase - chemistry; Crystallography, X-Ray; homology modeling; Humans; inhibition; Models, Molecular; molecular dynamics; Molecular Sequence Data; Sequence Homology, Amino Acid
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200600158

A homology model of human choline kinase (CK‐α) based on the X‐ray crystallographic structure of C. elegans choline kinase (CKA‐2) is presented. Molecular dynamics simulations performed on CK‐α confirm the quality of the model, and also support the putative ATP and choline binding sites. A good correlation between the MD results and reported CKA‐2 mutagenesis assays has been found for the main residues involved in catalytic activity. Preliminary docking studies performed on the CK‐α model indicate that inhibitors can bind to the binding sites of both substrates (ATP and choline). A possible reason for inhibition of choline kinase by Ca2+ ion is also proposed. A homology model of human choline kinase (CK‐α) is presented. Molecular dynamics simulations confirm its quality and support the putative ATP (red) and choline (green) binding sites. MD results are concordant with reported C. elegans choline kinase (CKA‐2) mutagenesis. Preliminary docking studies indicate that inhibitors (white) can bind into both binding sites.