3D-QSAR, Molecular Docking And Molecular Dynamics Simulations Studies On LSD1 Inhibitors

Histone lysine specific demethylases(LSD1)is an flavin adenine dinucleotide(FAD)dependent amino oxidase,and could specifically catalyzes the demethylation of monomethyl and dimethyl(not trimethyl)lysine residues H3K4 and H3K9.Many researches have proved that the overexpression of LSD1 in cells is related to the generation and development of multiple cancers and the heart development.Down regulating the expression and activity with RNA interference and LSD1 inhibitors could control the multiplication,metastasis and invasion of tumor cells.Meanwhile,the anti-tumor therapy of targeting LSD1 exhibited high selectivity and low toxic and side effect.Hence,LSD1 could be a new target for epigenetics anti-tumor drugs.There have been some small molecular LSD1 inhibitors showed good activity against tumor in vitro experiment,but the structure-activity relationship and interactions between LSD1 and these inhibitors were not clear,and the theoretical researches were lacking.It was significant to study the structure-activity relationship and interactions between LSD1 and LSD1 inhibitors using 3D-QSAR,molecular docking and molecular dynamics simulations for our novel drug design.In this article,three series of LSD1 inhibitors were selected to perform our molecular modeling study using comparative of molecular field analysis(CoMFA),comparative molecular similarity index analysis(CoMSIA),molecular docking and molecular dynamics simulations.And after calculation,the QSAR models with good statistical parameter and predictive ability were built and some key residues during the binding process were identified.These results would provide us new idea on the design of LSD1 inhibitors with hign selectivity and activity.This article was consisted with five sections.In chapter one,we would introduce the structure and physiological function of LSD1 in brief.Then we introduced the reseach progress on the LSD1 inhibitors and the representative LSD1 inhibitors.We would give some background of computer-aided drug design,including calculation method,calculation theory and softwares.And we would introduce our research focus.In chapter two,a series of 6-aryl-5-cyano-pyrimidine derivatives LSD1 inhibitors,which could bind to the FAD binding site of LSD1,were selected to perform a molecular modeling study using 3D-QSAR,molecular docking and molecular dynamics simulations.We study the proposed binding mode between ligands and LSD1.Based on the docking result,we build the 3D-QSAR models with good statistical parameters and reliable predictive ability.We test the stability of LSD1-ligand complexes using molecular dynamics simulations.And we find some key residues in the binding process using MM-PBSA method and energy decomposition.In chapter three,a series of pyridine containing LSD1 inhibitors,which could bind to the substrate binding site of LSD1,were selected to perform a molecular modeling study using 3D-QSAR,molecular docking and molecular dynamics simulations.We study the proposed binding mode between ligands and LSD1.Based on the docking result,we build the 3D-QSAR models with good statistical parameters and reliable predictive ability.We test the stability of LSD1-ligand complexes using molecular dynamics simulations.And we find some key residues in the binding process using MM-PBSA method and energy decomposition.In chapter four,a series of(4-Cyanophenyl)glycine derivatives LSD1 inhibitors,which could also bind to the substrate binding site of LSD1,were selected to perform a molecular modeling study using 3D-QSAR,molecular docking and molecular dynamics simulations.We study the proposed binding mode between ligands and LSD1.Based on the docking result,we build the 3D-QSAR models with good statistical parameters and reliable predictive ability.We test the stability of LSD1-ligand complexes using molecular dynamics simulations.And we find some key residues in the binding process using MM-PBSA method and energy decomposition.In chapter five,the essay has summed up what has been done and its prospect.