当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY期刊下所有文献 > Elaboration of a fragment library hit produces potent and selective aspartate semialdehyde dehydrogenase inhibitors.

Elaboration of a fragment library hit produces potent and selective aspartate semialdehyde dehydrogenase inhibitors.

Abstract：

:Aspartate-β-semialdehyde dehydrogenase (ASADH) lies at the first branch point in the aspartate metabolic pathway which leads to the biosynthesis of several essential amino acids and some important metabolites. This pathway is crucial for many metabolic processes in plants and microbes like bacteria and fungi, but is absent in mammals. Therefore, the key microbial enzymes involved in this pathway are attractive potential targets for development of new antibiotics with novel modes of action. The ASADH enzyme family shares the same substrate binding and active site catalytic groups; however, the enzymes from representative bacterial and fungal species show different inhibition patterns when previously screened against low molecular weight inhibitors identified from fragment library screening. In the present study several approaches, including fragment based drug discovery (FBDD), inhibitor docking, kinetic, and structure-activity relationship (SAR) studies have been used to guide ASADH inhibitor development. Elaboration of a core structure identified by FBDD has led to the synthesis of low micromolar inhibitors of the target enzyme, with high selectivity introduced between the Gram-negative and Gram-positive orthologs of ASADH. This new set of structures open a novel direction for the development of inhibitors against this validated drug-target enzyme.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Thangavelu B,Bhansali P,Viola RE

doi

10.1016/j.bmc.2015.09.017

subject

Has Abstract

pub_date

2015-10-15 00:00:00

pages

6622-31

issue

20

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(15)30042-0

journal_volume

23

pub_type

杂志文章

相关文献

BIOORGANIC & MEDICINAL CHEMISTRY文献大全
  • Design and pharmacophore modeling of biaryl methyl eugenol analogs as breast cancer invasion inhibitors.

    abstract：:Cell invasion and migration are required for the parent solid tumor cells to metastasize to distant organs. Microtubules form a polarized network, enabling organelle and protein movement throughout the cell. Cytoskeletal elements coordinately regulate cell's motility, adhesion, migration, exocytosis, endocytosis, and ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2009.12.019

    authors： Abdel Bar FM,Khanfar MA,Elnagar AY,Badria FA,Zaghloul AM,Ahmad KF,Sylvester PW,El Sayed KA

    更新日期：2010-01-15 00:00:00

  • Disulfide bridge cross-linking between protein and the RNA backbone as a tool to study RNase H1.

    abstract：:The chemical cross-linking of complexes of proteins with nucleic acids is often used in structural and mechanistic studies of these oftentimes unstable and transient complexes. To date, no method has been reported for the thiol-based conjugation of proteins with an RNA backbone, mainly because of instability of the mo...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2020.115741

    authors： Hyjek-Składanowska M,Stasińska AR,Napiórkowska-Gromadzka A,Bartłomiejczak A,Seth PP,Chmielewski MK,Nowotny M

    更新日期：2020-12-01 00:00:00

  • DNA sequence-specific recognition of peptides incorporating the HPRK and polyamide motifs.

    abstract：:Three peptide amides, HPRK(Py)(4)HPRK-NH(2) (PyH-12), HPRK(Py)(3)HPRK-NH(2) (PyH-11) and HPRK(Py)(2)HPRK-NH(2) (PyH-10), incorporating two HPRK motifs and various 4-amino-1-methylpyrrole-2-carboxylic acid residues (Py) were synthesized by solid-phase peptide methodology. The binding of these three peptides to a 5'-32P...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2003.10.049

    authors： Chang JC,Yang CH,Chou PY,Yang WH,Chou IC,Lu CT,Lin PH,Hou RC,Jeng KC,Cheng CC,Sheh L

    更新日期：2004-01-02 00:00:00

  • The synthesis and evaluation of phenoxyacylhydroxamic acids as potential agents for Helicobacter pylori infections.

    abstract：:Two series of ω-phenoxy contained acylhydroxamic acids as novel urease inhibitors were designed and synthesized. Biological activity evaluations revealed that ω-phenoxypropinoylhydroxamic acids were more active than phenoxyacetohydroxamic acids. Out of these compounds, 3-(3,4-dichlorophenoxy)propionylhydroxamic acid c...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2018.07.003

    authors： Ni WW,Liu Q,Ren SZ,Li WY,Yi LL,Jing H,Sheng LX,Wan Q,Zhong PF,Fang HL,Ouyang H,Xiao ZP,Zhu HL

    更新日期：2018-08-07 00:00:00

  • Controllable synthesis of polymerizable ester and amide prodrugs of acyclovir by enzyme in organic solvent.

    abstract：:A facile control of the acylation position at the primary hydroxyl and amino of acyclovir, respectively, was achieved and five polymerizable acyclovir prodrugs were synthesized. Various reaction conditions were studied in detail. Thus, lipase acrylic resin from Candida antarctica (CAL-B) in pyridine or acetone showed ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2005.12.050

    authors： Li X,Wu Q,Lv DS,Lin XF

    更新日期：2006-05-15 00:00:00

  • Studies on 3'-quaternary ammonium cephalosporins--IV. Synthesis and antibacterial activity of 3'-(2-alkyl-3-aminopyrazolium) cephalosporins related to FK037.

    abstract：:The synthesis and in vitro antibacterial activity of 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido] cephalosporins bearing various 2-alkyl-3-aminopyrazolium groups at the 3-position are described. Antibacterial activity against MRSA was affected by the nature of the substituent at the 2-position on the 3...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(97)00092-8

    authors： Ohki H,Kawabata K,Inamoto Y,Okuda S,Kamimura T,Sakane K

    更新日期：1997-08-01 00:00:00

  • Synthesis and biological evaluation of farnesylthiosalicylamides as potential anti-tumor agents.

    abstract：:Fourteen hybrids of farnesylthiosalicylic acid (FTS) with various diamines were synthesized and biologically evaluated. It was found that FTS-monoamide molecules (10a-g) displayed strong anti-proliferative activity against seven human cancer cell lines, superior to FTS and FTS-bisamide compounds (11a-g). The mono-amid...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2013.11.013

    authors： Ling Y,Wang Z,Zhu H,Wang X,Zhang W,Wang X,Chen L,Huang Z,Zhang Y

    更新日期：2014-01-01 00:00:00

  • Design, synthesis and pharmacological evaluation of (E)-3,4-dihydroxy styryl sulfonamides derivatives as multifunctional neuroprotective agents against oxidative and inflammatory injury.

    abstract：:A novel class of (E)-3,4-dihydroxy styryl sulfonamides and their 3,4-diacetylated derivatives as caffeic acid phenethyl ester (CAPE) analogs was designed and prepared for improving stability and solubility of the lead compound. Their neuroprotective properties were assessed by several models. The results showed that t...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2013.05.043

    authors： Ning X,Guo Y,Ma X,Zhu R,Tian C,Zhang Z,Wang X,Ma Z,Liu J

    更新日期：2013-09-01 00:00:00

  • Synthesis of 3-acyloxyxanthone derivatives as α-glucosidase inhibitors: A further insight into the 3-substituents' effect.

    abstract：:Considerable interest has been attracted in xanthone and its derivatives because of their important biological activities. In this paper, a series of novel 3-arylacyloxyxanthone derivatives 2a-p were synthesized and evaluated for their biological activities toward α-glucosidase. In comparison to the parent 1,3-dihydro...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2016.01.022

    authors： Li GL,Cai CY,He JY,Rao L,Ma L,Liu Y,Wang B

    更新日期：2016-04-01 00:00:00

  • Alkyl deoxy-arabino-hexopyranosides: synthesis, surface properties, and biological activities.

    abstract：:Octyl and dodecyl glycosides possessing 2-deoxy-arabino-hexopyranoside moieties belonging to the D- and L-series in their alpha- and beta-forms were synthesized by reaction of an acetyl protected glycal with octanol or dodecanol, catalyzed by triphenylphosphine hydrobromide, followed by deprotection. Their surface pro...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2008.01.020

    authors： Silva FV,Goulart M,Justino J,Neves A,Santos F,Caio J,Lucas S,Newton A,Sacoto D,Barbosa E,Santos MS,Rauter AP

    更新日期：2008-04-01 00:00:00

  • Arylazolyl(azinyl)thioacetanilides. Part 16: Structure-based bioisosterism design, synthesis and biological evaluation of novel pyrimidinylthioacetanilides as potent HIV-1 inhibitors.

    abstract：:A series of novel pyrimidinylthioacetanilides were designed, synthesized, and evaluated for their biological activity as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Most of the tested compounds were proved to be effective in inhibiting HIV-1 (IIIB) replication with EC50 ranging from 0.15 μM ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2014.08.001

    authors： Li X,Lu X,Chen W,Liu H,Zhan P,Pannecouque C,Balzarini J,De Clercq E,Liu X

    更新日期：2014-10-01 00:00:00

  • Synthesis and evaluation of N-substituted nipecotic acid derivatives with an unsymmetrical bis-aromatic residue attached to a vinyl ether spacer as potential GABA uptake inhibitors.

    abstract：:γ-Amino butyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS). A malfunction of the GABAergic neurotransmission is connected to several neuronal disorders like epilepsy, Alzheimer's disease, neuropathic pain, and depression. One possibility to enhance GABA levels in...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2013.02.056

    authors： Quandt G,Höfner G,Wanner KT

    更新日期：2013-06-01 00:00:00

  • Investigating the activity of 2-substituted alkyl-6-(2,5-dioxopyrrolidin-1-yl)hexanoates as skin penetration enhancers.

    abstract：:Skin penetration enhancers are used in the formulation of transdermal delivery systems for drugs that are otherwise not sufficiently skin-permeable. We generated two series of esters by multi-step synthesis with substituted 6-aminohexanoic acid as potential transdermal penetration enhancers by multi-step synthesis. Th...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2010.10.025

    authors： Brychtova K,Opatrilova R,Raich I,Kalinowski DS,Dvorakova L,Placek L,Csollei J,Richardson DR,Jampilek J

    更新日期：2010-12-15 00:00:00

  • Identification of a new selective dopamine D4 receptor ligand.

    abstract：:The dopamine D4 receptor has been shown to play key roles in certain CNS pathologies including addiction to cigarette smoking. Thus, selective D4 ligands may be useful in treating some of these conditions. Previous studies in our laboratory have indicated that the piperazine analog of haloperidol exhibits selective an...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2014.04.026

    authors： Sampson D,Zhu XY,Eyunni SV,Etukala JR,Ofori E,Bricker B,Lamango NS,Setola V,Roth BL,Ablordeppey SY

    更新日期：2014-06-15 00:00:00

  • Benzhydrylquinazolinediones: novel cytosolic phospholipase A2alpha inhibitors with improved physicochemical properties.

    abstract：:The synthesis and optimization of a class of trisubstituted quinazoline-2,4(1H,3H)-dione cPLA(2)alpha inhibitors are described. Utilizing pharmacophores that were found to be important in our indole series, we discovered inhibitors with reduced lipophilicity and improved aqueous solubility. These compounds are active ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2009.05.027

    authors： Kirincich SJ,Xiang J,Green N,Tam S,Yang HY,Shim J,Shen MW,Clark JD,McKew JC

    更新日期：2009-07-01 00:00:00

  • Synthesis and antiproliferative activity of sulfonamide-based peptidomimetic calpain inhibitors.

    abstract：:The calpains are a conserved family of cysteine proteases that includes several isoforms of which µ-calpain and m-calpain are the most widely distributed in mammalian cells. Calpains have been implicated in normal physiological processes as well as cellular abnormalities such as neurodegenerative disorders, cataract, ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2020.115433

    authors： Donkor IO,Xu J,Liu J,Cameron K

    更新日期：2020-05-01 00:00:00

  • A new and efficient synthesis of substituted 6-[(2'-dialkylamino)ethyl] pyrimidine and 4-N,N-dialkyl-6-vinyl-cytosine derivatives and evaluation of their anti-rubella activity.

    abstract：:New 6-[(2'-dialkylamino)ethyl]-4(3H)-pyrimidinones were prepared by a multistep procedure starting from acetone dicarboxylic acid diethyl ester and urea derivatives. These compounds were used as starting materials to obtain 4-N,N-dialkyl-6-vinyl-pyrimidine derivatives by an unprecedented tandem C-6 side chain Hofmann-...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(02)00077-9

    authors： Saladino R,Ciambecchini U,Maga G,Mastromarino P,Conti C,Botta M

    更新日期：2002-07-01 00:00:00

  • Development of water-soluble 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents.

    abstract：:In this work, four series of tertiary amine-containing derivatives of 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents were prepared, and their in vitro antimycobacterial effects were evaluated. We found that the studied compounds showed lipophilicity-dependent antimycobacterial activity. The N-benzylp...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2017.08.010

    authors： Roh J,Karabanovich G,Vlčková H,Carazo A,Němeček J,Sychra P,Valášková L,Pavliš O,Stolaříková J,Klimešová V,Vávrová K,Pávek P,Hrabálek A

    更新日期：2017-10-15 00:00:00

  • Activity landscape modeling of PPAR ligands with dual-activity difference maps.

    abstract：:Activation of peroxisome proliferator-activated receptor (PPAR) subtypes offers a promising strategy for the treatment of diabetes mellitus and metabolic diseases. Selective and dual PPAR agonists have been developed and the systematic characterization of their structure-activity relationships (SAR) is of major signif...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2012.04.005

    authors： Méndez-Lucio O,Pérez-Villanueva J,Castillo R,Medina-Franco JL

    更新日期：2012-06-01 00:00:00

  • Carbonic anhydrase inhibitors: inhibition of the human transmembrane isozyme XIV with a library of aromatic/heterocyclic sulfonamides.

    abstract：:The first inhibition study of the transmembrane carbonic anhydrase (CA, EC 4.2.1.1) isozymes hCA XIV with a library of aromatic and heteroaromatic sulfonamides synthesized earlier is reported. Most of the inhibitors were sulfanilamide, homosulfanilamide and 4-aminoethyl-benzenesulfonamide derivatives, to which tails t...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2005.06.022

    authors： Ozensoy O,Nishimori I,Vullo D,Puccetti L,Scozzafava A,Supuran CT

    更新日期：2005-11-15 00:00:00

  • Melanogenesis inhibitors from the rhizomes of Alpinia officinarum in B16 melanoma cells.

    abstract：:The 80% aqueous acetone extract from the rhizomes of Alpinia officinarum, a Chinese medicinal herb, were found to inhibit melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells. Among the constituents isolated, four diarylheptanoids [5-hydroxy-1,7-diphenyl-3-heptanone, 7-(4('')-hydroxy-3('')-methoxyphe...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2009.06.057

    authors： Matsuda H,Nakashima S,Oda Y,Nakamura S,Yoshikawa M

    更新日期：2009-08-15 00:00:00

  • A genetically selected cyclic peptide inhibitor of BCL6 homodimerization.

    abstract：:We report an inhibitor of the homodimeric protein-protein interaction of the BCL6 oncoprotein, identified from a genetically encoded SICLOPPS library of 3.2 million cyclic hexapeptides in combination with a bacterial reverse two-hybrid system. This cyclic peptide is shown to bind the BTB domain of BCL6, disrupts its h...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2018.03.012

    authors： Osher EL,Castillo F,Elumalai N,Waring MJ,Pairaudeau G,Tavassoli A

    更新日期：2018-07-15 00:00:00

  • DNA double helix destabilizing properties of cyclobisintercaland compounds and competition with a single strand binding protein.

    abstract：:The DNA helix destabilizing activity of a series of cyclobisintercaland compounds (CBIs) has been evaluated by measuring their ability to displace a 32P-labelled oligonucleotide primer (17-mer) hybridized to the single stranded DNA of M13. This destabilizing activity appears to be strongly dependent on the cyclic stru...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(99)00283-7

    authors： Teulade-Fichou MP,Fauquet M,Baudoin O,Vigneron JP,Lehn JM

    更新日期：2000-01-01 00:00:00

  • CC-1065 CBI analogs: an example of enhancement of DNA alkylation efficiency through introduction of stabilizing electrostatic interactions.

    abstract：:The three trimethylammonium salts 3-5 proved to be 100 times more efficient at alkylating DNA than 2 and exhibited DNA alkylation efficiencies identical to that of (+)-CC-1065 (1). In addition, the agents 3 and 4 exhibited DNA alkylation selectivities identical to that of 2. This may be attributed to spatially well-de...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/0968-0896(95)00048-l

    authors： Boger DL,Yun W,Han N,Johnson DS

    更新日期：1995-06-01 00:00:00

  • Dose dependent actions of LCL521 on acid ceramidase and key sphingolipid metabolites.

    abstract：:The function of acid ceramidase (ACDase), whose congenital deficiency leads to Farber disease, has been recognized to be vital to tumor cell biology, and inhibition of its activity may be beneficial in cancer therapy. Therefore, manipulation of the activity of this enzyme may have significant effect, especially on can...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2018.11.012

    authors： Bai A,Bielawska A,Rahmaniyan M,Kraveka JM,Bielawski J,Hannun YA

    更新日期：2018-12-15 00:00:00

  • From anti-fouling to biofilm inhibition: new cytotoxic secondary metabolites from two Indonesian Agelas sponges.

    abstract：:Chemical investigation of Indonesian marine sponges Agelas linnaei and A. nakamurai afforded 24 alkaloid derivatives representing either bromopyrrole or diterpene alkaloids. A. linnaei yielded 16 bromopyrrole alkaloids including 11 new natural products with the latter exhibiting unusual functionalities. The new compou...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2009.12.028

    authors： Hertiani T,Edrada-Ebel R,Ortlepp S,van Soest RW,de Voogd NJ,Wray V,Hentschel U,Kozytska S,Müller WE,Proksch P

    更新日期：2010-02-01 00:00:00

  • 3- and 6-Substituted 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridines as A1 adenosine receptor allosteric modulators and antagonists.

    abstract：:A series of 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridines were prepared and evaluated as potential allosteric modulators at the A(1) adenosine receptor. The structure-activity relationships of the 3- and 6-positions of a series of 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridines were explored. Despite finding that ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2009.08.024

    authors： Aurelio L,Valant C,Figler H,Flynn BL,Linden J,Sexton PM,Christopoulos A,Scammells PJ

    更新日期：2009-10-15 00:00:00

  • Synthesis and biological evaluation of cis-restrained carbocyclic combretastatin A-4 analogs: Influence of the ring size and saturation on cytotoxic properties.

    abstract：:Combretastatin A-4 (CA-4) is a highly cytotoxic natural product and several derivatives have been prepared which underwent clinical trial. These investigations revealed that the cis-stilbene moiety of the natural product is prone to undergo cis/trans isomerization under physiological conditions, reducing the overall a...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2019.07.048

    authors： Nowikow C,Fuerst R,Kauderer M,Dank C,Schmid W,Hajduch M,Rehulka J,Gurska S,Mokshyna O,Polishchuk P,Zupkó I,Dzubak P,Rinner U

    更新日期：2019-10-01 00:00:00

  • Computer-aided analysis of the interactions of glutamine synthetase with its inhibitors.

    abstract：:Mechanism of inhibition of glutamine synthetase (EC 6.3.1.2; GS) by phosphinothricin and its analogues was studied in some detail using molecular modeling methods. Among three possible conformations of phosphinothricin in the active site of GS, this compatible with binding mode of methionine sulfoximine, determined re...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2006.02.022

    authors： Berlicki L,Kafarski P

    更新日期：2006-07-01 00:00:00

  • Solution NMR analysis of the binding mechanism of DIVS6 model peptides of voltage-gated sodium channels and the lipid soluble alkaloid veratridine.

    abstract：:Voltage-gated sodium channels (VGSCs) are responsible for generating action potentials in nervous systems. Veratridine (VTD), a lipid soluble alkaloid isolated from sabadilla lily seed, is believed to bind to segment 6 of VGSCs and act as a partial agonist. However, high resolution structural interaction mechanism bet...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2012.03.034

    authors： Yoshinaka-Niitsu A,Yamagaki T,Harada M,Tachibana K

    更新日期：2012-05-01 00:00:00