Application Of Molecular Dynamics Simulation In Drug Design

The target of drug molecules is usually protein,and the recognition and binding of the target is the main way for small drug molecules to exert their pharmacological effects.Therefore,the study of drug-protein interaction mechanism plays a key role in the process of drug design.However,the conformations of proteins and drugs are often flexible and changeable,and this variability has a huge impact on the binding affinity of drugs.Therefore,it is very necessary to fully evaluate the structure and action mechanism of protein-drugs,and the usual experimental methods cannot adequately sample the protein conformation.As a powerful simulation calculation method,molecular dynamics simulation can be used to study proteins and drugs.The conformational changes and dynamics mechanisms of small molecules have been widely used in drug design.The small molecule drugs currently on the market account for a relatively large proportion.In the design of small molecule drugs,the simulation evaluation of the drugtarget mechanism is extremely important.Here we selected two protein systems,the Nterminal domain of Heat Shock Protein 90 and Sirtuin 6 and their corresponding small molecule drugs to carry out research.N-HSP90 is considered to be an important target for the treatment of cancer-related diseases.When combined with different inhibitors,it showed different binding affinity and showed loop in,loop out or helix conformation in the α-helix3 region.However,no helix conformation was observed in the crystal structure of apo-N-HSP90,and the kinetic mechanism between the conformational transition between helix-loop and ligand binding was not clear.In this paper,the molecular mechanism of inhibitor dissociation was investigated by combining molecular dynamicss and steered molecular dynamicss methods with the structures of two resorcinol complexes.The results showed that the introduction of side chain tetrahydrofuran groups of 6FJ inhibitors increases the interaction with key residues such as N106 and F138,which leads to higher binding affinity.In the process of inhibitor dissociation,the disruption of the interaction between 6FJ and N106 and F138 residues will cause the helix-loop transition of the α-helix 3 region.This conclusion has important reference significance for drug design.For example,the introduction of negatively charged groups similar to tetrahydrofuran in the side chain can increase the binding affinity of the drug.SIRT6 belongs to the SIRT deacetylase family and can deacetylate histone.SIRT6,also known as "multifaceted" protein,is involved in many important biochemical processes and is a potential target for the treatment of aging and other diseases.However,in the natural state,the deacetylase activity of SIRT6 is very low,the research progress on SIRT6 agonists is limited,and the activation mechanism of agonists is still unclear.In this paper,the activation mechanism of SIRT6 agonist CL5 D was studied by means of molecular dynamicss,random acceleration dynamicss and umbrella sampling.The results showed that the binding of agonist CL5 D can not only stabilize the conformation of the protein,but also reduce the dissociation barrier of the product.In addition,we also studied the agonist MDL-801.The results showed that the main function of MDL-801 is to stabilize the protein conformation,and there is no significant reduction in the dissociation barrier of the product,which indicates that there are many activation mechanisms of SIRT6 agonists.The research results help people understand the activation mechanism of SIRT6 agonists from a dynamics and atomic level.In summary,this research combined knowledge of biological information and chemical information,with molecular dynamicss simulation and enhancement sampling,Taking two proteins,N-HSP90 and SIRT6,as the research objects,the mechanism of action of drugs and proteins is deeply studied,and this interaction is described in detail from the perspective of atoms and kinetics.The research results in this article could provide important references for the design of drugs.