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.
Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia. knikolic@pharmacy.bg.ac.rs
Katarina
K
Nikolic
Nevena
N
Veljkovic
Branislava
B
Gemovic
Tatjana
T
Srdic-Rajic
Danica
D
Agbaba
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D054755:Imidazoline Receptors / Q000819:agonists* / Q000037:antagonists & inhibitors*; D020014:K562 Cells; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D000077769:Rilmenidine; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D008024:Ligands; D010080:Oxazoles; C410887:imidazoline I1 receptors; C043482:moxonidine; C062597:efaroxan; D000077769:Rilmenidine