Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study

The group of imidazoline-1 receptors (I1-IR) agonists encompasses drugs are currently used in treatment of high blood pressure and hyperglycemia. The I1-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 I1-IR candidate. In this study we examined apoptotic activity of rilmenidine (potent I1-IR agonist), moxonidine (moderate I1-IR agonist), and efaroxan (I1-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 3DQuantitative Structure-Activity Relationship (3D-QSAR) and virtual docking studies of 29 I1-IR ligands (agonists, partial agonists, and antagonists) were carried out on I1-IR receptors binding affinities. The 3D-QSAR study defined 3Dpharmacophore models for I1-IR agonistic and I1-IR antagonistic activity and created regression model for prediction of I1-IR activity of novel compounds. The 3D-QSAR models were applied for design and evaluation of novel I1-IR agonists and I1-IR antagonists. The most promising I1-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 I1-IR agonists (Arg 758, Arg 866, Val 981, and Glu 1057) and significantly different binding modes of I1-IR antagonists or partial I1-IR agonists. The performed theoretical study provides reliable system for evaluation of I1-IR agonistic and I1-IR antagonistic activity of novel I1-IR ligands, as drug candidates with anticancer activities.