Computer-aided Drug Molecular Design For Osteoporosis-related Targets

Osteoporosis is characterized by reduced bone mass,degeneration of bone micro-structure,increased bone fragility,and ultimately induced fractures.The incidence and prevalence of osteoporosis and osteoporotic fractures increased significantly,which will cause serious economic losses and family burden.Although there are many drugs for the treatment of osteoporosis on the market currently,they are limited.Therefore,the development of safer,more effective drugs with less side effects and the search for new osteoporosis targets are still the focus of osteoporosis research.Recent studies have identified new targets for osteoporosis,including anti-bone resorption targets,bone-promoting targets,and targets that are both anti-bone resorption and bone-promoting.Inhibitors of these targets can be used as potential drugs for the treatment of osteoporosis.Although osteoporosis target inhibitors have made some progress in the study of synthesis and pharmacological activity,their structure-activity relationship and interaction between molecules and target proteins are less studied.Therefore,in this study,we selected glycogen synthase kinase-3（GSK-3）and its inhibitors,cathepsin K（CTSK）and its inhibitors and cannabinoid type I receptor（CB1）and its inhibitors,through Three-dimensional quantitative structure-activity relationship（3D-QSAR）,pharmacophore and molecular docking methods in drug design,and a series of new compounds with higher inhibitory activity were designed to provide a theoretical basis for the study of osteoporosis targets.In the first chapter,we briefly introduced the concept of osteoporosis,advances in the treatment of osteoporosis,and osteoporosis-related targets（GSK-3 target,CTSK target,and CB1 target）and their inhibitors.Then introduced the basic knowledge of3D-QSAR,pharmacophores and molecular docking methods in computer-aided drug design.Finally,the significance of the topic is explained.In the second chapter,we constructed a well-predicted CoMFA model with 30 GSK-3inhibitors(q²=0.664,r²=0.990,r²_pred=0.774).We constructed CoMSIA model(q²=0.773,r²=0.989,r²_pred=0.583)and a rational pharmacophore model.We have found that a group with a positively charged or hydrogen bond acceptor is added to the C₃,C₅ and N atoms of the physicoline ring on the left side of the most active compound,and a hydrophobic group or an intermediate pyrrole is added to the F atom of the left benzene ring.The addition of a negatively charged group to the ring will increase the activity of the compound.Secondly,the molecular docking method was used to obtain the binding mode of the inhibitor molecule to the GSK-3 target protein,and it was found that Asp133 and Val135 play a key role in the binding of the inhibitor molecule to the GSK-3 protein.Finally,we designed 10new GSK-3 inhibitors with higher activity.In the third chapter,we selected 29 kinds of CTSK inhibitors and studied them with3D-QSAR,pharmacophores and molecular docking.A CoMFA model with stable prediction ability(q²=0.625,r²=0.985,r²_pred=0.763)and a CoMSIA model(q²=0.755,r²=0.992,r²_pred=0.808)were established by 3D-QSAR.Combining the QSAR model with the pharmacophore model,we found that adding a positively charged group at the C₃,C₄position of the highest active molecule or adding a hydrophobic or hydrogen bond acceptor group at the C₅ position of the benzene ring can effectively enhance the inhibition activity.In addition,the application of molecular docking technology found that Cys25,Gln19,Trp184 are key amino acids for the binding of compounds to CTSK target proteins.We modified the structure of the highest active compound to design 10 new compounds with better inhibitory activity against CTSK.In the fourth chapter,we combined 3D-QSAR,pharmacophore and molecular docking methods to study the structure-activity relationship of 31 CB1 inhibitors.The 3D-QSAR model we constructed has reliable predictive power:CoMFA model(q²=0.655,r²=0.986,r²_pred=0.774)and CoMSIA model(q²=0.656,r²=0.987,r²_pred=0.583).We analyzed the results of the QSAR model and the pharmacophore model and found that the C₄ position on the right benzene ring of the highest activity compound increases the electron donating group,the hydrogen bond acceptor group,the hydrophobic group or the benzene ring on the right side.Addition of a group containing a hydrogen bond acceptor at the C₅ position will facilitate an increase in activity.In addition,by analyzing the results of molecular docking,we found that Ser383 plays a key role in the binding of CB1 inhibitors to receptor proteins.Finally,we designed nine new CB1 inhibitors with higher predictive activity.The fifth chapter summarizes and forecasts the research of this thesis.