Virtual Screening Of Novel Lead Compounds Based On DGAT1 And SGK1 Targets

Obesity is an important cause of incidence rate and mortality worldwide,which has become a major public health problem.Diacylglyceryl acyltransferase 1（DGAT1）is a key enzyme in the synthesis of triacylglycerol in many organisms.The results of DGAT1 gene knocked out or enzyme activity inhibited revealed that the body will not be obese due to high-fat diet,and insulin sensitivity is enhanced.Serum/glucocorticoid-regulated kinase1（SGK1）plays important roles in the formation of glomerulosclerosis and interstitial fibrosis in diabetes nephropathy.Therefore,DGAT1 and SGK1 kinase have become important targets for obesity and diabetes treatment.Based on this,this investigation will apply computer-aided drug design and molecular dynamics methods to discover new inhibitors of DGAT1 and SGK1.The main contents of this thesis include:Chapter 1 Reviews the research.The research background,structure and function of DGAT1 and SGK1,inhibitors of DGAT1 and SGK1,computer-aided drug design methods,molecular dynamics simulation,research content and scheme were introduced.Chapter 2 Discovery of DGAT1-targeted inhibitors by virtual screening.In this investigation,the machine learning method,pharmacophore model and three-dimensional quantitative structure activity relationship（3D-QSAR）model were combined to discover novel DGAT1 inhibitors.Firstly,the SVM,NB and RP prediction models and common efficacy characteristic models for DGAT1 inhibitors were constructed,and further used to screen new DGAT1 inhibitors.Then,12 compounds with better properties were obtained.The surface charge and isosurface properties of the hits were analyzed by using the established 3D-QSAR model.Finally,8 hits with potential activity against SGK1 were obtained.Chapter 3 Discovery of novel SGK1 inhibitors by virtual screening,biological activity,and molecular dynamics simulation.In this investigation,the virtual screening method,including machine learning method,pharmacophore model,molecular docking,molecular dynamics simulation,and biological evaluation,was applied to discover novel SGK1 inhibitors.Firstly,the Bayesian classification model,pharmacophore model,and molecular docking methods were established.Secondly,the screened compounds were further evaluated by ADME/T,PAINS and drug-likeness analysis.Finally,28 compounds with potential activity were selected.The results of SGK1 kinase inhibition activity test revealed that among the 28 compounds,the hit15 compound displayed better activity,which gave 44.79%inhibition rate at the concentration of 10μM.The interaction mechanism between hit15 and SGK1 kinase was investigated by molecular dynamics simulation.Molecular dynamics simulations demonstrated that hit15 could stably bind to the active site of SGK1,and form a stable interaction with the key residues Ile179 and Val112.The binding free energy of SGK1-hit15 is-48.90±11.67k J·mol^-1.These above results suggest that screened hit15 is a new inhibitor with potential activity against SGK1kinase.Chapter 4 Conclusion and prospect.In this investigation,virtual screening of inhibitors targeting for DGAT1 and SGK1 kinase was carried out by employing computer-aided drug design technology.The main results are as follows:（1）8 novel DGAT1inhibitors with potential activity were discovered by machine learning method,pharmacophore model and 3D-QSAR model.（2）The virtual screening platform for SGK1 inhibitors was successfully constructed by combining machine learning,pharmacophore model,and molecular docking.28 SGK1 inhibitors with novel skeleton structure were selected,and the hit15 compound exhibited 44.79%inhibition rate at the concentration of 10μM.Molecular dynamics simulations displayed that hit15 can stably bind to the active site of SGK1.In summary,the new inhibitors discovered in this study can provide more new lead compounds for the development of anti-obesity drugs.In summary,obesity has become a worldwide public health problem.DGAT1 and SGK1 kinases were considered as important targets for the obesity treatment.In this investigation,8 novel inhibitors of DGAT1 and 1 novel inhibitor of SGK1 were screened by using computer virtual screening method,and molecular simulation,which would provide more new lead compounds for obesity treatment.