Imidazoline-1 receptor ligands as apoptotic agents: pharmacophore modeling and virtual docking study

The group of imidazoline-1 receptors (I(1)-IR) agonists encompasses drugs are currently used in treatment of high blood pressure and hyperglycemia. The I(1)-IR protein structures have not been determined yet, but Nischarin protein that binds numerous imidazoline ligands inducing initiation of various cell-signaling cascades, including apoptosis, is identified as strong I(1)-IR candidate. In this study we examined apoptotic activity of rilmenidine (potent I(1)-IR agonist), moxonidine (moderate I(1)-IR agonist), and efaroxan (I(1)-IR partial agonist) on cancer cell line (K562) expressing Nischarin. The Nischarine domains mapping was performed by use of the Informational Spectrum Method (ISM). The 3D-Quantitative Structure-Activity Relationship (3D-QSAR) and virtual docking studies of 29 I(1)-IR ligands (agonists, partial agonists, and antagonists) were carried out on I(1)-IR receptors binding affinities. The 3D-QSAR study defined 3D-pharmacophore models for I(1)-IR agonistic and I(1)-IR antagonistic activity and created regression model for prediction of I(1)-IR activity of novel compounds. The 3D-QSAR models were applied for design and evaluation of novel I(1)-IR agonists and I(1)-IR antagonists. The most promising I(1)-IR ligands with enhanced activities than parent compounds were proposed for synthesis. The results of 3D-QSAR, ISM, and virtual docking studies were in perfect agreement and allowed precise definition of binding mode of I(1)-IR agonists (Arg 758, Arg 866, Val 981, and Glu 1057) and significantly different binding modes of I(1)-IR antagonists or partial I(1)-IR agonists. The performed theoretical study provides reliable system for evaluation of I(1)-IR agonistic and I(1)-IR antagonistic activity of novel I(1)-IR ligands, as drug candidates with anticancer activities.