Imidazoline-1 Receptor Ligands as apoptotic agents: Pharmacophore Modeling and Virtual Docking study.

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 3D-Quantitative 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 3D-pharmacophore 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. PMID: 23360165 [PubMed - as supplied by publisher]
Source: Combinatorial Chemistry and High Throughput Screening - Category: Chemistry Authors: Tags: Comb Chem High Throughput Screen Source Type: research