Peptide design of a competitive inhibitor for HMG-CoA reductase based on statin structure.
This study investigates a proposed design of a peptide sequence that is based on a bioactive conformation of statins that act as the competitive inhibitors of HMG-CoA for HMGR. To bridge these heterogeneous organic compounds, a conformational aspect relating to an analysis of the flexibility of the peptide molecules and their occupied volumes was applied to the peptide design. The design criterion was formulated in terms of a proximity parameter (Pr), reflecting the probability of an active peptide conformation to approximate the statin. Through a structure-functional analysis of previously synthesized peptides and statin molecules, nine peptides were selected for the peptide library. Comparing the calculated proximity parameters, four peptides (IAVE, YAVE, IVAE, and YVAE) from the library were selected and synthesized. In vitro assays elucidated the inhibition properties for HMGR that are exhibited by these peptides. Among all peptides, YVAE showed the highest ability to inhibit HMGR. A kinetic analysis revealed that this peptide is a competitive inhibitor of HMG-CoA with an equilibrium constant of inhibitor binding (K(i)) of 15.2 +/- 1.4 microM. The calculated coefficient correlation (R) between log (IC(50)) and the inverse value of proximity parameter (1/Pr) was found to be 0.99, indicating a high degree of correlation and efficacy of the given approach in the peptide sequence design.
Pak
Valeriy V
VV
Food Function Research Division, Korea Food Research Institute, Seoul, Korea.
Kim
Sung Hee
SH
Koo
Minseon
M
Lee
Nari
N
Shakhidoyatov
K M
KM
Kwon
Dae Young
DY
D000595:Amino Acid Sequence; D001667:Binding, Competitive; D015195:Drug Design; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009842:Oligopeptides; D006903:Hydroxymethylglutaryl CoA Reductases