title: Molecular modeling and statistical analysis in the design of derivatives of human dipeptidyl peptidase IV.
abstract: Human dipeptidyl peptidase IV (hDDP-IV) has a considerable importance in inactivation of glucagon-like peptide-1, which is related to type 2 diabetes. One approach for the treatment is the development of small hDDP-IV inhibitors. In order to design better inhibitors, we analyzed 5-(aminomethyl)-6-(2,4-dichlrophenyl)-2-(3,5-dimethoxyphenyl)pyrimidin-4-amine and a set of 24 molecules found in the BindingDB web database for model designing. The analysis of their molecular properties allowed the design of a multiple linear regression model for activity prediction. Their docking analysis allowed visualization of the interactions between the pharmacophore regions and hDDP-IV. After both analyses were performed, we proposed a set of nine molecules in order to predict their activity. Four of them displayed promising activity, and thus, had their docking performed, as well as, the pharmacokinetic and toxicological study. Two compounds from the proposed set showed suitable pharmacokinetic and toxicological characteristics, and therefore, they were considered promising for future synthesis and in vitro studies.
authors.affiliation: a Laboratório de Pesquisas Forenses e Genômica, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto , University of São Paulo , Ribeirão Preto , Brazil.
authors.forename: Alison L E
authors.identifier: 0000-0002-0910-3976
authors.initials: ALE
authors.lastname: Pereira
authors.affiliation: b Computational Laboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto , University of São Paulo , Ribeirão Preto , São Paulo , Brazil.
authors.forename: Gabriela B
authors.initials: GB
authors.lastname: Dos Santos
authors.affiliation: b Computational Laboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto , University of São Paulo , Ribeirão Preto , São Paulo , Brazil.
authors.forename: Márcia S F
authors.initials: MSF
authors.lastname: Franco
authors.affiliation: b Computational Laboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto , University of São Paulo , Ribeirão Preto , São Paulo , Brazil.
authors.forename: Leonardo B
authors.initials: LB
authors.lastname: Federico
authors.affiliation: b Computational Laboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto , University of São Paulo , Ribeirão Preto , São Paulo , Brazil.
authors.forename: Carlos H T P
authors.initials: CHTP
authors.lastname: da Silva
authors.affiliation: b Computational Laboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto , University of São Paulo , Ribeirão Preto , São Paulo , Brazil.|c Laboratory of Modeling and Computational Chemistry, Department of Biological Sciences , Federal University of Amapá , 68902-280 Macapá , AP , Brazil.
authors.forename: Cleydson B R
authors.initials: CBR
authors.lastname: Santos
mesh_terms: D001665:Binding Sites; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000187:drug effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000627:therapeutic use; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D052216:Glucagon-Like Peptide 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
keywords: QSAR analysis; dipeptidyl peptidase IV; molecular modeling; pharmacokinetic and toxicological properties; statistical analysis