title: Docking-based 3D-QSAR study for selectivity of DPP4, DPP8, and DPP9 inhibitors.
abstract: In order to obtain information regarding the design of selective DPP4 inhibitors, a 3D-QSAR study was conducted using DPP4, DPP8, and DPP9 inhibitors including newly synthesized six- and seven-membered cyclic hydrazine derivatives (KR64300, KR64301), which were evaluated in vitro for their inhibition of DPP4, DPP8, and DPP9. In this study, a highly predictive CoMFA model based on the fast-docking for DPP4, DPP8, and DPP9 inhibitors was obtained. This reliable model showed leave-one-out cross-validation q(2) and conventional r(2) values of 0.68 and 0.96 for the DPP4 inhibitors, 0.58 and 0.98 for the DPP8 inhibitors, and 0.68 and 0.97 for the DPP9 inhibitors, respectively. The validation of the CoMFA model was confirmed by the compounds in the test set, including the synthesized six- and seven-membered cyclic hydrazines. According to this study, to obtain selective DPP4 inhibitors compared to their isozymes, the interaction of the inhibitors with the S3 site and S1' site in DPP4 must be considered. The proposed newly synthesized compounds, KR64300 and KR64301, interact well with the sites mentioned above, showing excellent selectivity.
authors.affiliation: Korea Research Institute of Chemical Technology, Yuseong-Gu, Daejeon 305-600, Republic of Korea. nskang@krict.re.kr <nskang@krict.re.kr>
authors.forename: Nam Sook
authors.initials: NS
authors.lastname: Kang
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Kim
authors.forename: Chong Hak
authors.initials: CH
authors.lastname: Chae
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Yoo
mesh_terms: D058892:Adenosine Deaminase Inhibitors; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004150:Dipeptidases / Q000037:antagonists & inhibitors*; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D015394:Molecular Structure; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D058892:Adenosine Deaminase Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D004150:Dipeptidases; C471241:DPP9 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C042807:DPP4 protein, human; C487997:DPP8 protein, human; D018819:Dipeptidyl Peptidase 4