HOMOLOGY MODELLING, DOCKING STUDY AND MOLECULAR DYNAMIC SIMULATION OF HUMAN SIRTUIN-7

• Main Author: Suwandi, Adi
• Format: Theses
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/78949
• Institution: Institut Teknologi Bandung

Histone deacetylases (HDACs) are a group of enzymes that remove acetyl group from histones which bind to DNA in nucleosome as a complex and hence involve in gene expression regulation. Sirtuin 7 (SIRT7) is a member of class Ill HDACs which in recent years has revealed its role in various cancers by in vitro and in vivo test and likely to be developed as a new anticancer target. At present, there is no experimental data related to the three-dimensional structure of the enzyme and also ,its inhibitor. The purpose of study was to generate the model of SIRT7 enzyme by homology modelling utilizing enzyme sequencp data that available in database, to conduct a docking simulation, and to run m61ecular dynamic simulation for predicting the interaction between enqme model and inhibitors. Model was generated with satisfication of spatial restraint method with Modeller v9.15 and threading method with I-TASSER@. Alignment was generated by pairwise sequences, multiple sequences, and profile-profile method to obtain the best model. Model's evaluation was conducted by assessing their streochemical and spatial properties. The best model chosen was used to run the optimization process and generate an enzim-cofactor complex with molecular dynamics simulations. The docking study was performed using the model obtained with inhibitors which have been developed for SIRTl and SIRT2 isoform. The docking results of SIRT7 model were compared against the results with the two others. Docking results of 53 compounds of three different classes of inhibitor showed that NAM6 and Ha29 are the best inhibitors for model SIRT7 enzyme. Docking results also showed that the value of free binding energy of NAM6 on SIRT7 ( 7.59 kcal/mol) is better than on SIRTI and SIRT2 (4.57 and-7.29 kcal/mol, respectively). Docking results on the three. enzymes also provided the informations about the difference of inhibitor binding feature on SIRT7 compared to SIRTl and SIRT2. Molecular dynamic simulation of the docking result of two complexes (inhibitor-SIRT7) showed that both inhibitors have stable interaction with the SIRT7.