The Investigation On The Interaction Mechanism Between β₂ Adrenergic Receptor And Ligands And Virtual Screening Of β Agonists

Chronic obstructive pulmonary disease（COPD）is a progressive chronic inflammatory disease characterized by persistent airflow limitation.Long actingβ-agonist（LABA）are effective drugs for the treatment of COPD,which can effectively relax airway smooth muscle and rapidly improve the symptoms of dyspnea and cough.However,due to the existence of large side effects and drug resistance,it is still urgent to develop drugs with high activity and toxic bottom.It is crucial to explore the molecular conformation characteristics ofβ₂-adrenergic receptor（β₂AR）,a drug target protein of airway smooth muscle,and to clarify the binding mechanism between receptor and drug.Crystallography revealed the activated metastable state of the proteinβ₂AR and the binding position of the ligand in its ion channel,helping people understand the molecular recognition and signal transmission process of the ligand-binding protein.However,it is still difficult to capture the dynamic structural characteristics of ligand activatedβ₂AR at the molecular level and elucidate the interaction mechanism of receptor signal transduction.Therefore,molecular simulation method has been used to explore the interaction mechanism and dynamic structural characteristics of the binding ofβ₂AR receptor and ligand.Drugs with potential for the treatment of COPD are screened,and their activity and efficacy are evaluated,which will help to design drugs that controlβ₂AR signaling more accurately.Firstly,Ligandfit molecular docking method was used,molecular dynamics simulation and binding free energy analysis were carried out,and anisotropic network model（ANM）was used to predict the vibrational motion mode of the receptor.The interaction mechanism of Indacaterol,Olodaterol and Formoterol withβ₂AR and the opening and closing mechanism of ion channels activated by the receptor were systematically studied.The results show that the three long-acting agonists can bind toβ₂AR receptor through hydrogen bonding,hydrophobic interaction andπ-πstacking interaction.The electrostatic interaction between receptor residues ASP192 and ASP300 and ligand plays a key role in ligand receptor binding.At the same time,the prediction results of ANM model show that the opening and closing of the ligand binding pocket ofβ₂AR and the opening and closing of the ion channel are not simultaneous,but are realized by the highly coordinated opening and closing of the symmetrical subunits,especially the vibration of subunits TM5 and TM6.These results provide the necessary theoretical basis for further study of the interaction mechanism and signal transduction mechanism betweenβ₂AR and drugs.Secondly,the conformation change and activation mechanism of g-C₃N₄ modified Indacatrol binding toβ₂AR were studied by molecular simulation method,in order to explore the interaction mechanism between nanoparticles and receptors.The results show that Indacatrol is first adsorbed in the active pocket of the receptor when the g-C₃N₄ and the ligand are simultaneously placed near theβ₂AR binding pocket.Subsequently,g-C₃N₄forms a stable inverted triangle"grid"in the binding cavity,which tightens the binding pocket through hydrogen bonding andπ-πstacking interaction,and Indacatrol fully interacts with the residues of the receptor active site,so as to prevent the ligand from being separated from the solution environment during the binding process.However,due to the limited space position of the binding pocket,with the increase of g-C₃N₄ adsorbed in the binding pocket,the competition between the ligand and the nanoparticles is formed due to the steric hindrance effect,resulting in the weakening of the interaction between the ligand and the receptor,which is not conducive to the ligand receptor binding.Thirdly,eight activeβ-agonists were used to construct and verify the pharmacophore model based on the common molecular characteristics,and the candidate compounds with higher scores than the training set were obtained through virtual screening in ZINC database.Based on the ADMET method,eight compounds with the highest activity were obtained,and the geometric structures of the lead compounds were optimized.Based on Libdock method,the best binding mode between ligand and receptor was found,and the affinity and stability of compounds and receptors were evaluated.The results showed that the optimal pharmacophore had aromatic center,hydrogen bond receptor and hydrophobic group,which could match with eightβ-agonists.The eight ligands showed a certain degree of drug activity,and had high affinity and stability withβ₂AR receptor,which are potential good drugs for the treatment of COPD.Fourth,high-performance computers have become an indispensable tool for scientific research.Due to the influence of environmental factors or conditions,most servers cannot be installed in the standard computer room.If it is stored in a bad environment for a long time,the dust pollutants in the air accumulate in the interior,the ventilation is not smooth,the heat dissipation rate slows down,and the internal temperature of the chassis is high,it will lead to service failure,and even affect the service life of the server.Because the server cluster will overheat in the process of long-time computing,overheat will not only reduce the efficiency of CPU,but also damage the server equipment.Therefore,this paper provides an electrostatic precipitator and a server water cooling cabinet for solving the existing technical problems and improving the equipment conditions.