Document Type
Article
Publication Date
1-2013
Source Publication
Biochemical and Biophysical Research Communications
Source ISSN
0006-291X
Abstract
Phosphomevalonate kinase (PMK) phosphorylates mevalonate-5-phosphate (M5P) in the mevalonate pathway, which is the sole source of isoprenoids and steroids in humans. We have identified new PMK inhibitors with virtual screening, using autodock. Promising hits were verified and their affinity measured using NMR-based 1H–15N heteronuclear single quantum coherence (HSQC) chemical shift perturbation and fluorescence titrations. Chemical shift changes were monitored, plotted, and fitted to obtain dissociation constants (Kd). Tight binding compounds with Kd’s ranging from 6–60 μM were identified. These compounds tended to have significant polarity and negative charge, similar to the natural substrates (M5P and ATP). HSQC cross peak changes suggest that binding induces a global conformational change, such as domain closure. Compounds identified in this study serve as chemical genetic probes of human PMK, to explore pharmacology of the mevalonate pathway, as well as starting points for further drug development.
Recommended Citation
Boonsri, Pornthip; Neumann, Terrence S.; Olson, Andrew Lawrence; Cai, Sheng; Herdendorf, Timothy J.; Miziorko, Henry M.; Hannongbua, Supa; and Sem, Daniel S., "Molecular Docking and NMR Binding Studies to Identify Novel Inhibitors of Human Phosphomevalonate Kinase" (2013). Chemistry Faculty Research and Publications. 376.
https://epublications.marquette.edu/chem_fac/376
Comments
Accepted version. Biochemical and Biophysical Research Communications, Vol. 430, No. 1 (January 2013): 313-319. DOI. © 2013 Elsevier. Used with permission.
NOTICE: this is the author’s version of a work that was accepted for publication in Biochemical and Biophysical Research Communications. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Biochemical and Biophysical Research Communications, VOL 430, ISSUE 1, January 4, 2013: DOI.