Study On The Tructure-Activity Relationship Of Phosphodiesterase 4B Inhibitor

Inflammation is an important immune defense mechanism of organism.Generally,inflammation acts as a normal physiological response of body to injuries and/or infections.However,persisting inflammation is likely to cause problems,leading to damages to the injured/infected tissues.There are variety of diseases that involve inflammation,from COVID-19,arthritis and diabetes to chronic obstructive pulmonary disease,asthma,lupus cancer and so on.Therefore,the development of anti-inflammatory drugs is vitally important.In recent years,phosphodiesterase 4B(PDE4B)has attracted much attention as an important medicinal target of anti-inflammatory drugs.Phosphodiesterase 4B specific inhibitors can avoid side effects such as nausea and vomiting associated with phosphodiesterase 4(PDE4)inhibitor drugsand it is expected to become a drug for the treatment of inflammatory diseases.In this thesis,the structure-activity and structure-selectivity relationships of PDE4 inhibitors were investigated by a series of studies including quantitative structure-activity analysis,molecular docking,molecular dynamics simulation,binding free energy calculation and energy decomposition.These researches provide valuable information for the design of PDE4B inhibitors with high activity and selectivity.The contents of chapters are described blow.In Chapters One,I firstly reviewed the structure and physiological effects PDE4 subtypes,PDE4 inhibitors as a new generation of anti-inflammatory drugs for the treatment of Alzheimer’s disease,depression,chronic obstructive pulmonary disease,asthma and psoriasis.Then,the recent advance of PDE4B inhibitors is introduced and the future development of PDE4B-specific inhibitors is prospected.In Chapter Two,the relationship between molecular structure and activity of phenyl-furan derivatives PDE4B/PDE4D inhibitors was studied based on ligands’structures.First,the Comparative Molecular Field Analysis(CoMFA)was performed to study the structure-activity relationship of PDE4B/PDE4D inhibitors.The influence of different charge schemes on CoMFA model was investigated.These results showed the best predictions with q~2=0.794,r~2=0.987for PDE4B inhibitors and q~2=0.700,r~2=976 for PDE4D inhibitors were obtained by using MMFF94 and Gasteiger charge schemes,respectively.According to the resulted 3-D CoMFA maps,we predicted that increasing the substituent size or introducing strong electron donating groups near the 4-phenyl moiety should increase the biological activity of PDE4B inhibitors.We performed Topomer CoMFA analysis on 2-D ligands structures and discussed the influence of different cutting on the predictions the Topomer CoMFA model.This analysis showed that for both PDE4B and PDE4D inhibitors the best prediction is achieved by using two-fragments cutting analysis.The predictions obtained from Topomer CoMFA are consistent with the ones from CoMFA.According to the structure-activity relationship obtained above,we designed eight PDE4B inhibitor molecules with high activity.In Chapters Three,the binding of different inhibitors with PDE4B/PDE4D was investigated by using various receptor-based methods.First,we selected 20PDE4B-inhibitor and 41 PDE4D-inhibitor crystal complexes to estimate the correlations between the ligands’inhibition activities and ligand-receptor binding free energies predicted by Auto Dock or Vina programs.Regression analysis showed Vina surpass the Auto Dock with corresponding coefficients of r=0.34 for PDE4B inhibitors and r=0.51 for PDE4D inhibitors vs the ones of r=0.26 for PDE4B inhibitors and r=0.29 for PDE4D inhibitors.Using Vina prediction method,regression analysis show that optimize the hydrogen of receptor surpass not optimize with corresponding coefficients of r=0.34 for PDE4B inhibitors and r=0.51 for PDE4D inhibitors vs the ones of r=0.12 for PDE4B inhibitors and r=0.44 for PDE4D inhibitors.Then,the binding free energies of eight compounds with PDE4B/PDE4D were calculated by MM/GB(PB)SA method.The effects of different simulation time,different dielectric constant,different charge scheme of ligand and calculation methods of binding free energy on the calculated values were compared.Regression analysis show that in the simulation period of 40-50ns,the dielectric constantε=2,MM/GBSA method is used to calculate binding free energy with corresponding coefficients of r=0.65 for PDE4B inhibitors and r=0.64 for PDE4D inhibitors.On the base,the key amino acids related to binding energy were identified by energy decomposition method.The factors leading to the PDE4B-selectivity were studied by using energy decomposition and amino acid mutation.These calculations suggested that Ile410,Gln443,Phe446 and Phe506 contributed significantly to the selectivity of inhibitors.Finally,the future development of PDE4B inhibitors is prospected based on the work of this thesis.The present studies provide new ideas for the design of PDE4B inhibitor with potent activity and high selectivity.