title: Probing the interaction mechanism of small molecule inhibitors with matriptase based on molecular dynamics simulation and free energy calculations.
abstract: Matriptase is a serine protease associated with a wide variety of human tumors and carcinoma progression. Up to now, many promising anti-cancer drugs have been developed. However, the detailed structure-function relationship between inhibitors and matriptase remains elusive. In this work, molecular dynamics simulation and binding free energy studies were performed to investigate the biochemistry behaviors of two class inhibitors binding to matriptase. The binding free energies predicted by MM/GBSA methods are in good agreement with the experimental bioactivities, and the analysis of the individual energy terms suggests that the van der Waals interaction is the major driving force for ligand binding. The key residues responsible for achieving strong binding have been identified by the MM/GBSA free energy decomposition analysis. Especially, Trp215 and Phe99 had an important impact on active site architecture and ligand binding. The results clearly identify the two class inhibitors exist different binding modes. Through summarizing the two different modes, we have mastered some important and favorable interaction patterns between matriptase and inhibitors. Our findings would be helpful for understanding the interaction mechanism between the inhibitor and matriptase and afford important guidance for the rational design of potent matriptase inhibitors.
authors.affiliation: b Institute of Theoretical Chemistry, Jilin University , Changchun 130023 , P.R. China.
authors.forename: Dong-Ru
authors.initials: DR
authors.lastname: Sun
authors.affiliation: a Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education , Jilin University , Changchun , Jilin 130023 , P.R. China.|b Institute of Theoretical Chemistry, Jilin University , Changchun 130023 , P.R. China.
authors.forename: Qing-Chuan
authors.initials: QC
authors.lastname: Zheng
authors.affiliation: b Institute of Theoretical Chemistry, Jilin University , Changchun 130023 , P.R. China.
authors.forename: Hong-Xing
authors.initials: HX
authors.lastname: Zhang
mesh_terms: D020134:Catalytic Domain; D004347:Drug Interactions; D006801:Humans; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D012697:Serine Endopeptidases; C485595:matriptase
keywords: MM–GBSA calculation; matriptase; molecular dynamic simulation; small molecule inhibitors