Pharmacophore modeling and molecular docking studies of acridines as potential DPP-IV inhibitors

Inhibition of dipeptidyl peptidase-IV (DPP-IV) prevents the inactivation of gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). This increases circulating levels of active GLP-1 and GIP and stimulates insulin secretion, which results in lowering of glucose levels and improvement of the glycemic control in patients with type 2 diabetes. In this study, pharmacophore modeling and docking experiments were carried out and a series of eight novel 2-ethoxy-6,9-disubstituted acridines (13,15, and 17a-17f) have been designed and synthesized. Then, these compounds were evaluated for their ability to inhibit DPP-IV. Most of the synthesized compounds were proven to have anti-DPP-IV activity where compound 17b displayed the best activity of 43.8% inhibition at 30 µmol/L concentration. Results of this work might be helpful for further optimization to develop more potent DPP-IV inhibitors. Key words: acridines, diabetes, docking, DPP-IV inhibitors, pharmacophore modeling. L'inhibition de la dipeptidylpeptidase-4 (DPP-4) empeche l'inactivation du peptide insulinotrope dependant du glucose (GIP) et du glucagon-like peptide-1 (GLP-1). Il en resulte une augmentation des concentrations de GLP-1 et de GIP actifs en circulation ainsi qu'une stimulation de la secretion d'insuline, qui entraine a son tour une baisse de la concentration de glucose et une amelioration de la maitrise de la glycemie chez les patients atteints de diabete de type 2. Dans la presente etude, nous avons realise des experiences de modelisation du pharmacophore et de simulation d'amarrage et nous avons elabore et synthetise une serie de huit 2-ethoxy-6,9-acridines disubstituees (13, 15 et 17a-17f). Nous avons ensuite evalue ces composes quant a leur capacite d'inhiber la DPP-4. La plupart des composes synthetises ont montre une activite anti-DPP-4; parmi ceux-ci, le compose 17b a presente la meilleure activite, soit 43,8 % d'inhibition a une concentration de 30 µmol/L. Les resultats de ces travaux pourraient contribuer a faire progresser l'optimisation de ces composes en vue de creer des inhibiteurs de la DPP-4 plus puissants. [Traduit par la Redaction] Mots-cles: acridines, diabetes, amarrage, inhibiteurs de la DPP-4, modelisation de pharmacophore.
Introduction Diabetes is a chronic disease that occurs either when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. (1) Hyperglycemia [...]