TITLE

Elucidating the structural basis of diphenyl ether derivatives as highly potent enoyl-ACP reductase inhibitors through molecular dynamics simulations and 3D-QSAR study

AUTHOR(S)
Kamsri, Pharit; Punkvang, Auradee; Saparpakorn, Patchareenart; Hannongbua, Supa; Irle, Stephan; Pungpo, Pornpan
PUB. DATE
July 2014
SOURCE
Journal of Molecular Modeling;Jul2014, Vol. 20 Issue 7, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Diphenyl ether derivatives are good candidates for anti-tuberculosis agents that display a promising potency for inhibition of InhA, an essential enoyl-acyl carrier protein (ACP) reductase involved in fatty acid biosynthesis pathways in Mycobacterium tuberculosis. In this work, key structural features for the inhibition were identified by 3D-QSAR CoMSIA models, constructed based on available experimental binding properties of diphenyl ether inhibitors, and a set of four representative compounds was subjected to MD simulations of inhibitor-InhA complexes for the calculation of binding free energies. The results show that bulky groups are required for the R substituent on the phenyl A ring of the inhibitors to favor a hydrophobic pocket formed by residues Phe149, Met155, Pro156, Ala157, Tyr158, Pro193, Met199, Val203, Leu207, Ile215, and Leu218. Small substituents with a hydrophilic property are required at the R and R positions of the inhibitor phenyl B rings to form hydrogen bonds with the backbones of Gly96 and Met98, respectively. For the R substituent, small substituents with simultaneous hydrophilic or hydrophobic properties are required to favor the interaction with the pyrophosphate moiety of NAD and the methyl side chain of Ala198, respectively. The reported data provide structural guidance for the design of new and potent diphenyl ether-based inhibitors with high inhibitory activities against M. tuberculosis InhA. [Figure not available: see fulltext.]
ACCESSION #
97165413

 

Related Articles

  • Aqueous Molecular Dynamics Simulations of the M. tuberculosis Enoyl-ACP Reductase-NADH System and Its Complex with a Substrate Mimic or Diphenyl Ethers Inhibitors. da Silva Lima, Camilo Henrique; de Alencastro, Ricardo Bicca; Kaiser, Carlos Roland; de Souza, Marcus Vinícius Nora; Rodrigues, Carlos Rangel; Albuquerque, Magaly Girão // International Journal of Molecular Sciences;2015, Vol. 16 Issue 10, p23695 

    Molecular dynamics (MD) simulations of 12 aqueous systems of the NADH-dependent enoyl-ACP reductase from Mycobacterium tuberculosis (InhA) were carried out for up to 20-40 ns using the GROMACS 4.5 package. Simulations of the holoenzyme, holoenzyme-substrate, and 10 holoenzyme-inhibitor complexes...

  • Docking analysis of substituted pyrazoles as M. tuberculosis Enoyl ACP reductase inhibitors. Purnima, S.; Subashini, S.; Subhashini, N.; Solairaj, P. // Der Pharmacia Sinica;2013, Vol. 4 Issue 1, p88 

    Tuberculosis continues to be a major cause of morbidity and mortality all over the world. No new drug has been developed in the past 30 yr. Consequently, there is an urgent need to identify new drug targets in mycobacteria and eventually, develop new drugs. The enoyl acyl carrier protein...

  • N-Substituted 2-Isonicotinoylhydrazinecarboxamides — New Antimycobacterial Active Molecules. Rychtarčíková, Zuzana; Krátký, Martin; Gazvoda, Martin; Komlóová, Markéta; Polanc, Slovenko; Kočevar, Marijan; Stolaříková, Jiřina; Vinšová, Jarmila // Molecules;Apr2014, Vol. 19 Issue 4, p3851 

    This report presents a new modification of the isoniazid (INH) structure linked with different anilines via a carbonyl group obtained by two synthetic procedures and with N-substituted 5-(pyridine-4-yl)-1,3,4-oxadiazole-2-amines prepared by their cyclisation. All synthesised derivatives were...

  • Sequence-motif Detection of NAD(P)-binding Proteins: Discovery of a Unique Antibacterial Drug Target. Yun Hao Hua; Chih Yuan Wu; Sargsyan, Karen; Lim, Carmay // Scientific Reports;9/26/2014, p1 

    Many enzymes use nicotinamide adenine dinucleotide or nicotinamide adenine dinucleotide phosphate (NAD(P)) as essential coenzymes. These enzymes often do not share significant sequence identity and cannot be easily detected by sequence homology. Previously, we determined all distinct locally...

  • Mutations upstream of fabI in triclosan resistant Staphylococcus aureus strains are associated with elevated fabI gene expression. Grandgirard, Denis; Furi, Leonardo; Ciusa, Maria Laura; Baldassarri, Lucilla; Knight, Daniel R.; Morrissey, Ian; Largiadèr5, Carlo R.; Leib, Stephen L.; Oggioni, Marco R. // BMC Genomics;2015, Vol. 16 Issue 1, p1 

    Background: The enoyl-acyl carrier protein (ACP) reductase enzyme (FabI) is the target for a series of antimicrobial agents including novel compounds in clinical trial and the biocide triclosan. Mutations in fabI and heterodiploidy for fabI have been shown to confer resistance in S. aureus...

  • DESIGNING AND SCREENING OF POTENT INHIBITOR AGAINST INHA REDUCTASE OF MYCOBACTERIUM TUBERCULOSIS: A COMPUTATIONAL APPROACH. DEVI, URIKHIMBAM JOYLAXMI; CHETIA, PANKAJ; DEVI, THOKCKOM ANITA; CHOUDHURY, MANABENDRA DUTTA // Asian Journal of Pharmaceutical & Clinical Research;2014, Vol. 7 Issue 2, p161 

    Objectives: In this study, we attempt to design potent inhibitor specifically targeting the enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis. Methods: In silico docking studies were performed using FlexX and Autodock Vina with ligand1 (library compound) and known inhibitors...

  • Structure-based Design Of Benzophenone Inhibitors Targeting Enoyl-ACP Reductase Enzyme. Ramana, M. M. V.; Lokhande, R. S.; Joshi, Urmila J.; Gadre, Gayatri V.; Joshi, Akshada J. // International Journal of Pharmaceutical Sciences Review & Resear;May/Jun2014, Vol. 26 Issue 1, p134 

    Mycobacterium leprae is the causative agent of the disease, leprosy. As M. leprae develops resistance against most of the drugs, novel drug targets are required in order to design new drugs. The present study is aimed at finding the active site of the protein, which is used as a strategy in drug...

  • Synthesis, Docking, and Antibacterial Activity of Some Novel 4-Substituted s-triazino[1,2-a]benzimidazoles. Ammar, Yousry A.; El-Sehrawi, Hend M.; El-Zahabi, Heba S. A.; Shawer, Taghreed Z.; Ismail, Magda M. F. // Der Pharma Chemica;2012, Vol. 4 Issue 5, p2140 

    Two novel series of 2-amino-3,4-dihydro[1,3,5]triazino[1,2-a]benzimidazoles, and 2-amino-4,4-disubstituted/- spiro[1,3,5]triazino[1,2-a]benzimidazoles were synthesized and evaluated for their in vitro antibacterial activity against Staphylococcus aureus and Escherichia coli. Molecular modeling...

  • Isolation and characterization of an enoyl-acyl carrier protein reductase gene from microalga Isochrysis galbana. Zheng, Minggang; Liang, Kepeng; Wang, Bo; Sun, Xiuqin; Yue, Yanyan; Wan, Wenwen; Zheng, Li // Chinese Journal of Oceanology & Limnology;Mar2013, Vol. 31 Issue 2, p398 

    In most bacteria, plants and algae, fatty acid biosynthesis is catalyzed by a group of freely dissociable proteins known as the type II fatty acid synthase (FAS II) system. In the FAS II system, enoylacyl carrier protein reductase (ENR) acts as a determinant for completing the cycles of fatty...

Share

Read the Article

Courtesy of VIRGINIA BEACH PUBLIC LIBRARY AND SYSTEM

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics