Quantitative structure–activity relationship modeling of renin-inhibiting dipeptides
- 371 Downloads
Partial least squares regression method was used to analyze a peptide dataset and construct inhibitory models for renin-inhibitory natural dipeptides. The models were computed with the renin-inhibitory activity as dependent variable (Y) and the peptide structural properties as predictors (X); validation was conducted using cross-validation and permutation tests. The amino acid descriptors were based on the 3- and 5-z scales of 20 coded amino acids to produce models that explained 71.6% of Y with a 33.8% predictive ability and 75.2% of Y with a predictive power of 50.8%, respectively. In both models, low molecular size amino acids with hydrophobic side chains were preferred at the N-terminus, while amino acids with bulky side chains were preferred at the C-terminus for potency. Based on the 5-z model, four Trp (W)-containing antihypertensive dipeptides (IW, LW, VW and AW) were predicted as the most potent renin inhibitors. The peptides were synthesized and in vitro inhibition assay showed that IW and LW inhibited 70% (IC50, 2.3 mM) and 37% renin activity at 3.2 mM, respectively, whereas VW and AW were inactive. There was no correlation between the observed renin-inhibitory activities and angiotensin-converting enzyme inhibitory activities of the dipeptides. We concluded that the structural similarities between isoleucine and leucine could have contributed to their distinct inhibitory activity when compared to alanine and valine. Therefore, IW may be a useful template for the development of advanced forms of highly active low molecular size antihypertensive peptides and peptidomimetics.
KeywordsRenin inhibitors Dipeptides Quantitative structure–activity relationship (QSAR) Partial least squares regression (PLS) Amino acid descriptors
Operating and equipment research grants for this project were provided to Dr. RE Aluko by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Advanced Foods and Materials Network of Centre of Excellence (AFMNet) Canada. CC Udenigwe is a recipient of NSERC Alexander Graham Bell Canada PhD Scholarship.
- Aluko RE (2008) Antihypertensive properties of plant-derived inhibitors of angiotensin I-converting enzyme activity: a review. In: Govil JN, Singh VK (eds) Recent progress in medicinal plants—phytopharmacology and therapeutic values IV, vol 22. Stadium Press, Houston, TX, pp 541–561Google Scholar
- Dunn WJ III, Wold S (1995) SIMCA pattern recognition and classification. In: van de Waterbeemd H (ed) Chemometrics methods in molecular design. VCH VerlagsgesellshaftmbH, Weinheim, pp 179–193Google Scholar
- Li H (2010) Identification and characterization of bioactive peptides derived from pea protein. PhD Dissertation. University of ManitobaGoogle Scholar
- Sato M, Hosokawa T, Yamaguchi T, Nakano T, Muramoto K, Kahara T, Funayama K, Kobayashi A, Nakano T (2002) Angiotensin I-converting enzyme inhibitory peptides derived from wakame (Undaria pinnatifida) and their antihypertensive effect in spontaneously hypertensive rats. J Agric Food Chem 50:6245–6252PubMedCrossRefGoogle Scholar
- SIMCA-P 11 Software Analysis Advisor (2005) Umetrics AB, Umeå, SwedenGoogle Scholar