Identification of novel natural inhibitor for NorM – a multidrug and toxic compound extrusion transporter – an insilico molecular modeling and simulation studies. Issue 1 (2nd January 2017)

• Record Type: Journal Article
• Authors: Kesherwani, Manish; Michael Gromiha, M.; Fukui, Kazuhiko; Velmurugan, Devadasan
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 35:Issue 1(2017)
• Page Start: 58
• Page End: 77
• Publication Date: 2017-01-02
• Subjects: MATE -- drug design -- molecular dynamics simulation -- efflux mechanism -- binding free energy -- Neisseria gonorrhea; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2015.1132391
• Languages: English
• ISSNs: 0739-1102

Abstract

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.