title: In silico approaches to predict the potential of milk protein-derived peptides as dipeptidyl peptidase IV (DPP-IV) inhibitors.
abstract: Molecular docking of a library of all 8000 possible tripeptides to the active site of DPP-IV was used to determine their binding potential. A number of tripeptides were selected for experimental testing, however, there was no direct correlation between the Vina score and their in vitro DPP-IV inhibitory properties. While Trp-Trp-Trp, the peptide with the best docking score, was a moderate DPP-IV inhibitor (IC50 216μM), Lineweaver and Burk analysis revealed its action to be non-competitive. This suggested that it may not bind to the active site of DPP-IV as assumed in the docking prediction. Furthermore, there was no significant link between DPP-IV inhibition and the physicochemical properties of the peptides (molecular mass, hydrophobicity, hydrophobic moment (μH), isoelectric point (pI) and charge). LIGPLOTs indicated that competitive inhibitory peptides were predicted to have both hydrophobic and hydrogen bond interactions with the active site of DPP-IV. DPP-IV inhibitory peptides generally had a hydrophobic or aromatic amino acid at the N-terminus, preferentially a Trp for non-competitive inhibitors and a broader range of residues for competitive inhibitors (Ile, Leu, Val, Phe, Trp or Tyr). Two of the potent DPP-IV inhibitors, Ile-Pro-Ile and Trp-Pro (IC50 values of 3.5 and 44.2μM, respectively), were predicted to be gastrointestinally/intestinally stable. This work highlights the needs to test the assumptions (i.e. competitive binding) of any integrated strategy of computational and experimental screening, in optimizing screening. Future strategies targeting allosteric mechanisms may need to rely more on structure-activity relationship modeling, rather than on docking, in computationally selecting peptides for screening.
authors.affiliation: Department of Life Sciences and Food for Health Ireland (FHI), University of Limerick, Castletroy, Limerick, Ireland.
authors.forename: Alice B
authors.initials: AB
authors.lastname: Nongonierma
authors.affiliation: School of Medicine and Medical Science, Complex and Adaptive Systems Laboratory and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Mooney
authors.affiliation: School of Medicine and Medical Science, Complex and Adaptive Systems Laboratory and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; Food for Health Ireland (FHI), University College Dublin, Belfield, Dublin 4, Ireland. Electronic address: Denis.shields@ucd.ie.
authors.forename: Denis C
authors.initials: DC
authors.lastname: Shields
authors.affiliation: Department of Life Sciences and Food for Health Ireland (FHI), University of Limerick, Castletroy, Limerick, Ireland. Electronic address: dick.fitzgerald@ul.ie.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: FitzGerald
mesh_terms: D020134:Catalytic Domain; D003198:Computer Simulation; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008894:Milk Proteins / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D008894:Milk Proteins; D010455:Peptides; D018819:Dipeptidyl Peptidase 4
keywords: Bioactive peptides; Dipeptidyl peptidase IV inhibitors; Hydrophobicity; Milk; Molecular docking; Predictive modeling