Design of nicotinic acetylcholine antagonists by virtual ligand screening method

A total of 14.8 million people in Turkey (27.1%) use tobacco products. Nicotine dependence is the first cause of continued smoking behavior and overall failure of treatment interventions. Nicotine, an alkaloid derived from the leaves of the Nicotiana tabacum plant, is a very easily absorbed substance and is easily and rapidly absorbed by the lungs, mouth, nose, skin. Nicotine is the main cause of cigarette dependence. The nicotinic acetylcholine receptor (nAChR) is an ion channel receptor, which is activated by acetylcholine and nicotine which is the main component of tobacco dependence. To date, 17 nACh receptor subunits have been identified, including muscarinic (α1, β1, γ, δ and ε) and neuronal (α2-α10 and β2-β4). The most widely distributed nAChR subunits in the central nervous system are α4β2 (~ 90%) and α7 (~ 10%) subunits. The α4β2 subunit is the target structure of smoking cessation drugs. Although there are several experimental studies (in vivo and in vitro) that some phytochemicals (camphor, menton, menthol, carvacrol, thymoquinone, flavonoids, etc.) in some plants (avena sativa, hypericum perforatum, lavandula stoechas, lobelia inflata, nigella sativa, piper nigrum) are smoking cessation features, there are no any studies with nAChR (nicotinic acetylcholine receptor) including binding properties and energy. Our aim is to investigate how some phytochemicals (camphor, menton, menthol, carvacrol, thymoquinone, flavonoids, etc.) in some plants (avena sativa, hypericum perforatum, lavandula stoechas, lobelia inflata, nigella sativa, piper nigrum) interact with nAChR as an antagonist by using Docking program Autodock Vina. In the first part of the study, the validation of the AutoDock Vina program was performed for AChBP (acetylcholine binding protein) 1UW6 and 2BYR. As a result of calculation, RMSD values for 1UW6 and 2BYR were found 1.3 and 1.6 Å respectively. Due to RMSD value is less than 2 Å, AutoDock Vina has been determined to be suitable for the selected system. In the second step, geometry optimization of phytochemicals in lavandula stoechas, avena sativa, piper nigrum, lobelia inflata, hypericum perforatum and nigella sativa were performed by DFT/B3LYP/6-31G(d,p) and the binding of phytochemicals to the active site of AChBP was analyzed by using the AutoDock Vina program. İt was found that miquelianin has the highest antagonist activity. In the last part of the study, virtual ligand screening study was performed for 506 compounds in ZINC15 database. Our calculation results showed that the first 20 structures showing the best binding affinity would be promising candidates. As a result of the research carried out in this thesis, the obtained data will contribute to the design of new candidate antagonists which may be effective as nAChR antagonists.