title: Identification of novel human dipeptidyl peptidase-IV inhibitors of natural origin (part I): virtual screening and activity assays.
abstract: BACKGROUND
  There has been great interest in determining whether natural products show biological activity toward protein targets of pharmacological relevance. One target of particular interest is DPP-IV whose most important substrates are incretins that, among other beneficial effects, stimulates insulin biosynthesis and secretion. Incretins have very short half-lives because of their rapid degradation by DPP-IV and, therefore, inhibiting this enzyme improves glucose homeostasis. As a result, DPP-IV inhibitors are of considerable interest to the pharmaceutical industry. The main goals of this study were (a) to develop a virtual screening process to identify potential DPP-IV inhibitors of natural origin; (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits; and (c) to use the most active hit for predicting derivatives with higher binding affinities for the DPP-IV binding site.
  
  
  RESULTS
  We predicted that 446 out of the 89,165 molecules present in the natural products subset of the ZINC database would inhibit DPP-IV with good ADMET properties. Notably, when these 446 molecules were merged with 2,342 known DPP-IV inhibitors and the resulting set was classified into 50 clusters according to chemical similarity, there were 12 clusters that contained only natural products for which no DPP-IV inhibitory activity has been previously reported. Nine molecules from 7 of these 12 clusters were then selected for in vitro activity testing and 7 out of the 9 molecules were shown to inhibit DPP-IV (where the remaining two molecules could not be solubilized, preventing the evaluation of their DPP-IV inhibitory activity). Then, the hit with the highest activity was used as a lead compound in the prediction of more potent derivatives.
  
  
  CONCLUSIONS
  We have demonstrated that our virtual-screening protocol was successful in identifying novel lead compounds for developing more potent DPP-IV inhibitors.
authors.affiliation: Grup de Recerca en Nutrigenòmica, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Campus de Sescelades, Tarragona, Catalonia, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Guasch
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Ojeda
authors.forename: Noemí
authors.initials: N
authors.lastname: González-Abuín
authors.forename: Esther
authors.initials: E
authors.lastname: Sala
authors.forename: Adrià
authors.initials: A
authors.lastname: Cereto-Massagué
authors.forename: Miquel
authors.initials: M
authors.lastname: Mulero
authors.forename: Cristina
authors.initials: C
authors.lastname: Valls
authors.forename: Montserrat
authors.initials: M
authors.lastname: Pinent
authors.forename: Anna
authors.initials: A
authors.lastname: Ardévol
authors.forename: Santiago
authors.initials: S
authors.lastname: Garcia-Vallvé
authors.forename: Gerard
authors.initials: G
authors.lastname: Pujadas
mesh_terms: D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D062126:Databases, Chemical; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D054795:Incretins / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D059748:Proteolysis / Q000187:drug effects
chemical_list: D001688:Biological Products; D054873:Dipeptidyl-Peptidase IV Inhibitors; D054795:Incretins; D018819:Dipeptidyl Peptidase 4