Study Of The Interaction Mechanism Between Drugs And Targets Based On Multi-level

Study of the interaction mechanism between drugs and targets plays a vital role during the development of drugs.Research on their interaction mechanisms not only has a very important significance for revealing the nature of biology,but also can improve the rational design capability of the precursor structure of the novel efficient inhibitors as well as the speed and accuracy of screening studies.In this work,using the molecular modeling and chemoinformatics approaches,we systematicly studied the interaction mechanisms between drugs and targets,diseases and pathways from single molecule and single target to multi-molecules and multi-targets at different levels.The main conclusions are listed as follows:(1)To understand the mechanism of actions between drugs and targets at one molecule and one target level,we take a series of TRPV1 antagonists as an example to construct the three-dimensional quantitative structure-activity relationship(3D-QSAR)model for guiding the drug design.Employing molecular docking technique,the mechanism of action of drugs and targets was analyzed and the potential binding modes of these antagonists within the active site of the receptor were also predicted accurately.Additinally,the kinetic process of drug-target interactions was explored by molecular dynamics(MD)simulation.These methods provided the theoretical studies on the modes of action between targets and small molecule drugs at the molecular level,offering a new idea for structural-based drug design.(2)To improve the efficiency and predictive ability of the constructed molecular model at one molecule and one target level,a novel rational division methodology based on a genetic algorithm(GA)was employed for building the 3D-QSAR models.Then,to confirm the rationality of the constructed model based on GA splitting approach,the corresponding model is also built by self-organizing maps and random division methods.The obtained results indicate that the model constructed by GA division method is more efficient and exert more significant statistical results,proving the reasonability of the GA division method for constucting the models.Thesefore,the GA splitting approach may help researchers to more quickly design a new and highly active drug molecule in the drug development.(3)To explore the interaction mechanism between drugs and targets at the multi-molecule and multi-target level,two natural medicines,i.e.,Semen Strychni and Tripterygium wilfordii Hook F(TwHF)for treating rheumatoid arthritis(RA)were used as a matter of example.Firstly,we built the ingredient database of these two natural medicines and screened out their active components using ADME screening models.Subsequently,the potential targets of these active compounds were predicted by using a computer simulation prediction model.In final,by constucting the interaction network of multi-component and multi-target,the underlying mechanism of Semen Strychni and TwHF in treating RA was analyzed and illuminated from the network level.Taken together,the design of multi-component and multi-target combination for specific complex diseases can improve the pharmacokinetic and pharmacodynamic properties of candidate drugs,providing a novel strategy for the natural medicine in treating complex diseases.(4)To investigate the molecular mechanism of synergistic action between the multi-component and multi-target of drugs in treating the complex diseases from a higher system level,in the present study,using a statistical method,we screened out seven anti-RA natural medicines except for Semen Strychni and TwHF,which include Radix Paeoniae Alba,Angelicae Sinensis Radix,Radix Angelicae Biseratae,Aconiti Lateralis Radix Praeparata,Cinnamomi Ramulus,Radix Astragali seu Hedysari and Anemarrhenae Rhizoma.Taking the formula consisted by these seven anti-RA natural medicines as an example,we firstly built their active ingredients database,identified their potential targets and constructed four networks including Compound-Target,Compound-Target-Function,Compound-Target-Disease and Target-Pathway networks.Then,a complete network pharmacological analysis for these herbs in the treatment of RA was carried out from the perspective of multiple scales.Subsquently,MD simulations and binding modes analysis were introduced to explore the binding modes between drugs and targets as well as their interaction mechnism.In addition,in vitro experiments by ligand binding assays validated whether the potential active compounds bind to the predicted targets,offering theoretical guidance for the development of new drugs for the treatment of complex diseases.