title: Identification of novel natural inhibitor for NorM - a multidrug and toxic compound extrusion transporter - an insilico molecular modeling and simulation studies.
abstract: The emergence of bacterial multidrug resistance is an increasing problem in treatment of infectious diseases. An important cause for the multidrug resistance of bacteria is the expression of multidrug efflux transporters. The multidrug and toxic compound extrusion (MATE) transporters are most recently recognized as unique efflux system for extrusion of antimicrobials and therapeutic drugs due to energy stored in either Na+or H+electrochemical gradient. In the present study, high throughput virtual screening of natural compound collections against NorM - a MATE transporter from Neisseria gonorrhea (NorM-NG) has been carried out followed by flexible docking. The molecular simulation in membrane environment has been performed for understanding the stability and binding energetic of top lead compounds. Results identified a compound from the Indian medicinal plant "Terminalia chebula" which has good binding free energy compared to substrates (rhodamine 6 g, ethidium) and more favorable interactions with the central cavity forming active site residues. The compound has restricted movement in TM7, TM8, and TM1, thus blocking the disruption of Na+ - coordination along with equilibrium state bias towards occlude state of NorM transporter. Thus, this compound blocks the effluxing pathway of antimicrobial drugs and provides as a natural bioactive lead inhibitor against NorM transporter in drug-resistant gonorrhea.
authors.affiliation: a Centre of Advanced Study in Crystallography and Biophysics , University of Madras , Guindy Campus, Chennai , India.
authors.forename: Manish
authors.initials: M
authors.lastname: Kesherwani
authors.affiliation: b Department of Biotechnology , IIT Madras , Chennai 600 036 , India.
authors.forename: M
authors.initials: M
authors.lastname: Michael Gromiha
authors.affiliation: c Molecular Profiling Research Center for Drug Discovery Data Management and Integration Team , National Institute of Advanced Industrial Science and Technology (AIST) , 2-4-7 Aomi Koto-ku, Tokyo 135-0064 , Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Fukui
authors.affiliation: a Centre of Advanced Study in Crystallography and Biophysics , University of Madras , Guindy Campus, Chennai , India.|d Bioinformatics Infrastructure Facility , University of Madras , Guindy Campus, Chennai 600025 , India.
authors.forename: Devadasan
authors.initials: D
authors.lastname: Velmurugan
mesh_terms: D017920:Antiporters / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology; D002412:Cations / Q000737:chemistry; D015195:Drug Design; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D012964:Sodium / Q000737:chemistry
chemical_list: D017920:Antiporters; D001426:Bacterial Proteins; D001688:Biological Products; D002412:Cations; D008024:Ligands; C114619:NorM protein, bacteria; D012964:Sodium
keywords: MATE; Neisseria gonorrhea; binding free energy; drug design; efflux mechanism; molecular dynamics simulation