title: Theoretical studies on the interaction of biphenyl inhibitors with Mycobacterium tuberculosis protein tyrosine phosphatase MptpB.
abstract: MptpB is an essential secreted virulence factor for M. tuberculosis. Inhibition of MptpB impairs mycobacterial survival in host macrophages and thus helps reduce tuberculosis infections. However, the binding mode of the biphenyl inhibitors, which are known as some of the most potent MptpB inhibitors, remains unclear. In this study, to understand the interactions between biphenyl inhibitors and MptpB, docking and molecular dynamics simulations were carried out using AutoDock and GROMACS softwares. Calculation results show that all the biphenyl inhibitors can be docked to the binding site of MptpB, with the acid warheads forming a hydrogen bond network at the active site. But the binding modes of other terminals of these inhibitors are different. The cyclohexyl and trifluoromethyl substituents at R1 and R2 sites are necessary for the inhibitors to adopt their double-site binding mechanism. The estimated binding affinities are basically consistent with the experimental results. MD simulations show that these binding complexes display different stability.
authors.affiliation: Key Laboratory of Adaptation and Evolution of Plateau Biota, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, 810001, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Dong
authors.forename: Junyou
authors.initials: J
authors.lastname: Shi
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001713:Biphenyl Compounds / Q000737:chemistry*; D020134:Catalytic Domain; D006860:Hydrogen Bonding; D007555:Isoxazoles / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D010757:Phosphorous Acids / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013816:Thermodynamics; D013844:Thiazoles / Q000737:chemistry
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001713:Biphenyl Compounds; D007555:Isoxazoles; C414465:MptpA protein, Mycobacterium tuberculosis; D010757:Phosphorous Acids; D013844:Thiazoles; C512915:isothiazolidinone; D017027:Protein Tyrosine Phosphatases