title: Discovery of DPP IV inhibitors by pharmacophore modeling and QSAR analysis followed by in silico screening.
abstract: Dipeptidyl peptidase IV (DPP IV) deactivates the natural hypoglycemic incretin hormones. Inhibition of this enzyme should restore glucose homeostasis in diabetic patients making it an attractive target for the development of new antidiabetic drugs. With this in mind, the pharmacophoric space of DPP IV was explored using a set of 358 known inhibitors. Thereafter, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and physicochemical descriptors that yield selfconsistent and predictive quantitative structure-activity relationships (QSAR) (r(2) (287)=0.74, F-statistic=44.5, r(2) (BS)=0.74, r(2) (LOO)=0.69, r(2) (PRESS) against 71 external testing inhibitors=0.51). Two orthogonal pharmacophores (of cross-correlation r(2)=0.23) emerged in the QSAR equation suggesting the existence of at least two distinct binding modes accessible to ligands within the DPP IV binding pocket. Docking experiments supported the binding modes suggested by QSAR/pharmacophore analyses. The validity of the QSAR equation and the associated pharmacophore models were established by the identification of new low-micromolar anti-DPP IV leads retrieved by in silico screening. One of our interesting potent anti-DPP IV hits is the fluoroquinolone gemifloxacin (IC(50)=1.12 muM). The fact that gemifloxacin was recently reported to potently inhibit the prodiabetic target glycogen synthase kinase 3beta (GSK-3beta) suggests that gemifloxacin is an excellent lead for the development of novel dual antidiabetic inhibitors against DPP IV and GSK-3beta.
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Amman, Jordan.
authors.forename: Ihab M
authors.initials: IM
authors.lastname: Al-Masri
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Mohammad
authors.forename: Mutasem O
authors.initials: MO
authors.lastname: Taha
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D024841:Fluoroquinolones / Q000737:chemistry; D000077735:Gemifloxacin; D005951:Glucose Tolerance Test; D006801:Humans; D054795:Incretins / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D009287:Naphthyridines / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D024841:Fluoroquinolones; D054795:Incretins; D009287:Naphthyridines; D018819:Dipeptidyl Peptidase 4; D000077735:Gemifloxacin