Urodynamics Studies On BPH Combined With Dm Or IFG And Molecular Dynamics Simulations Provide Insight Into Gleevec’s Selectivity Toward Human Tyrosine Kinases

Objective: To investigate the changes of urodynamics on benign prostatic hyperplasia combined with diabetes mellitus or impaired fasting glucose,and to provide a reasonable and operative therapy scheme.Methods: This study selected from October 2014 to October 2016 In The Second Hospital of Dalian Medical University uropoiesis surgical department through the urethra prostate electricity cut gouge or transurethral resection of prostate in addition to surgery,postoperative pathological diagnosis of benign prostatic hyperplasia and preoperative row urine flow dynamic test of 163 cases of patients,divided into the prostate hyperplasia 40 patients with diabetes mellitus(group 1),prostate hyperplasia combined impaired fasting glucose regulation(IFG)22 cases(group 2),simple hyperplasia of prostate,101 cases(control group).Comparing groups of patients with urine flow mechanics,the test results.Results: Unstable bladder rate of diabetes group and the control group,P value is 0.02.Impaired fasting glucose regulation unstable bladder rate comparison group and the control group,P value is 0.025.Diabetes and impaired fasting glucose regulation group of unstable bladder rate comparison,P value is 0.499.In diabetes group and the control group of Qmax,Pdet at Qmax,Pdet max,PVR,FDV detection index comparison,P values were 0.001,0.202,0.330,0.001,0.002;Of impaired fasting glucose regulation group and the control group of Qmax,Pdet at Qmax,Pdet max,PVR,FDV detection index comparison,P values were 0.008,0.171,0.153,0.191,0.012;In diabetes group and impaired fasting glucose regulation of Qmax,Pdet at Qmax,Pdet max,PVR,FDV detection index comparison,P values were 0.006,0.165,0.052,0.005,0.001.Conclusion: High blood glucose and hyperplasia of prostate has synergism effect on bladder function.For BPH patients with diabetes or impaired fasting glucose regulation with should be taken seriously,active treatment of BPH and at the same time as soon as possible to take reasonable and effective treatment measures to control the blood glucose levels.Protein kinases are critical drug targets against cancer.Since the discovery of Gleevec,a specific inhibitor of Abl kinase,the ability of this drug to distinguish between Abl and other tyrosine kinases such as Src has been intensely investigated but without much success.Here,we performed molecular dynamics(MD)simulations,dynamical cross correlation matrices(DCCM),dynamical network analysis,and binding free energy calculations to explore Gleevec’s selectivity based on crystal structures of Abl,Src and their common ancestors(ANC-AS)and the two constructed mutation systems(AS→Abl and AS→Src).MD simulations revealed that the conformation of the phosphate-binding loop(P-loop)altered significantly in the AS→Abl system.DCCM results unraveled that mutations led to an increase of anticorrelated motions in the AS→Abl system and community network analysis suggested that the P-loop established special contacts in the AS→Abl system,which are devoid in the AS→Src system.The binding free energy calculations unveiled that the affinity of Gleevec to AS→Abl increased to near the level of Abl and that to AS→Src decreased to near the level of Src.The individual residue contributions found that the differences located mainly at the P-loop.This study will be valuable for understanding Gleevec’s selectivity toward human tyrosine kinases.