Identification of new GATA4-small molecule inhibitors by structure-based virtual screening.


:Members of the GATA family of transcription factors are zinc finger proteins that were shown to play evolutionary conserved roles in cell differentiation and proliferation in different organisms. We hypothesized that by finding new molecules that inhibit their function to be crucial in future therapeutical interventions for various diseases. By virtual high throughput screening using a version of glide (Schrodinger®) program with both crystal and NMR structure of GATA C-terminal zinc finger, we identified new small molecular weight chemicals with lead-like properties. We used in vitro cell-based assays to show that these molecules selectively and efficiently inhibit GATA4 activity by inhibiting its interaction with the DNA. In addition we showed that these molecules can block the activation of downstream target genes by GATA4. Moreover these compounds can moderately enhanced a mouse model of myoblast differentiation into myotubes. This might be partially due to decreased GATA4/DNA interaction as shown by gel retardation assays. Further investigation is needed to reach selectivity and efficacy. Our study however do show that in silico screening combined with in vitro studies are efficient tools to unravel new molecules that interact with zinc finger proteins such as GATA4.


Bioorg Med Chem


El-Hachem N,Nemer G




Has Abstract


2011-03-01 00:00:00














  • Allosteric inhibitors of hepatitis C virus NS5B polymerase thumb domain site II: structure-based design and synthesis of new templates.

    abstract::Chronic hepatitis C virus (HCV) infections are a significant medical problem worldwide. The NS5B Polymerase of HCV plays a central role in virus replication and is a prime target for the discovery of new treatment options. We recently disclosed 1H-benzo[de]isoquinoline-1,3(2H)-diones as allosteric inhibitors of NS5B P...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Malancona S,Donghi M,Ferrara M,Martin Hernando JI,Pompei M,Pesci S,Ontoria JM,Koch U,Rowley M,Summa V

    更新日期:2010-04-15 00:00:00

  • Synthesis and binding affinities of methylvesamicol analogs for the acetylcholine transporter and sigma receptor.

    abstract::We synthesized methylvesamicol analogs 13-16 and investigated the binding characteristics of 2-[4-phenylpiperidino]cyclohexanol (vesamicol) and methylvesamicol analogs 13-16, with a methyl group introduced into the 4-phenylpiperidine moiety, to sigma receptors (sigma-1, sigma-2) and to vesicular acetylcholine transpor...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Shiba K,Ogawa K,Ishiwata K,Yajima K,Mori H

    更新日期:2006-04-15 00:00:00

  • Bromo-deaza-SAH: a potent and selective DOT1L inhibitor.

    abstract::Chemical inhibition of proteins involved in chromatin-mediated signaling is an emerging strategy to control chromatin compaction with the aim to reprogram expression networks to alter disease states. Protein methyltransferases constitute one of the protein families that participate in epigenetic control of gene expres...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Yu W,Smil D,Li F,Tempel W,Fedorov O,Nguyen KT,Bolshan Y,Al-Awar R,Knapp S,Arrowsmith CH,Vedadi M,Brown PJ,Schapira M

    更新日期:2013-04-01 00:00:00

  • The design and synthesis of a novel compound of berberine and baicalein that inhibits the efficacy of lipid accumulation in 3T3-L1 adipocytes.

    abstract::The combination of berberine and baicalein may have a better therapeutic effect against disease. To explore the combined effect of baicalein and berberine in the treatment of obesity, we designed and synthesized a hybrid compound, and its biological activities were evaluated in 3T3-L1 adipocytes. The structures of the...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Hao M,Li Y,Liu L,Yuan X,Gao Y,Guan Z,Li W

    更新日期:2017-10-15 00:00:00

  • Novel squaramides with in vitro liver stage antiplasmodial activity.

    abstract::A structure-activity relationship study was performed with ten 8-aminoquinoline-squaramides compounds active against liver stage malaria parasites, using human hepatoma cells (Huh7) infected by Plasmodium berghei parasites. In addition, their blood-schizontocidal activity was assessed against chloroquine-resistant W2 ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ribeiro CJ,Espadinha M,Machado M,Gut J,Gonçalves LM,Rosenthal PJ,Prudêncio M,Moreira R,Santos MM

    更新日期:2016-04-15 00:00:00

  • Directed evolution of N-acetylneuraminic acid aldolase to catalyze enantiomeric aldol reactions.

    abstract::Expanding the scope of substrate specificity and stereoselectivity is of current interest in enzyme catalysis. Using error-prone PCR for in vitro directed evolution, the Neu5Ac aldolase from Escherichia coli has been altered to improve its catalytic activity toward enantiomeric substrates including N-acetyl-L-mannosam...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Wada M,Hsu CC,Franke D,Mitchell M,Heine A,Wilson I,Wong CH

    更新日期:2003-05-01 00:00:00

  • Structure-based design of parasitic protease inhibitors.

    abstract::To streamline the preclinical phase of pharmaceutical development, we have explored the utility of structural data on the molecular target and synergy between computational and medicinal chemistry. We have concentrated on parasitic infectious diseases with a particular emphasis on the development of specific noncovale...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Li R,Chen X,Gong B,Selzer PM,Li Z,Davidson E,Kurzban G,Miller RE,Nuzum EO,McKerrow JH,Fletterick RJ,Gillmor SA,Craik CS,Kuntz ID,Cohen FE,Kenyon GL

    更新日期:1996-09-01 00:00:00

  • Enantioselective synthesis of (+)-4-demethoxy-1,4-dimethyldaunomycinone.

    abstract::(+)-4-Demethoxy-1,4-dimethyldaunomycinone 1 was synthesized using a convergent approach. Here, the key tetracyclic compound 10 was assembled by way of a Diels-Alder reaction using the sugar-based diene 8 and the quinizarin-related dienophile 7. ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Kotha S,Stoodley RJ

    更新日期:2002-03-01 00:00:00

  • Selective carriers of norepinephrine and ammonium ions: ionophoric properties and molecular modelling studies of diester crown compounds containing a 1,3-bis(1H-pyrazol-1-yl)propane unit.

    abstract::Ionophoric properties of dipyrazolic crowns and podands containing a 1,3-bis(1H-pyrazol-1-yl)propane unit in their structure are described. They show selectivity of ammonium vs alkali cations and interesting norepinephrine transport rates. A molecular modelling study has been used to elucidate the superstructures of t...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Rodríguez-Franco MI,Fierros M,Martínez A,Navarro P,Conde S

    更新日期:1997-02-01 00:00:00

  • Synthesis and structure activity relationships of novel non-peptidic metallo-aminopeptidase inhibitors.

    abstract::Racemic derivatives of 3-amino-2-tetralone were synthesised and evaluated for their ability to inhibit metallo-aminopeptidase activities. New compounds substituted in position 2 by methyl ketone, substituted oximes or hydroxamic acids as well as heterocyclic derivatives were evaluated against representative members of...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Albrecht S,Defoin A,Salomon E,Tarnus C,Wetterholm A,Haeggström JZ

    更新日期:2006-11-01 00:00:00

  • Development of sulfonamides incorporating phenylacrylamido functionalities as carbonic anhydrase isoforms I, II, IX and XII inhibitors.

    abstract::A series of novel sulfonamides incorporating phenylacrylamido functionalities were synthesized and investigated for the inhibition of the metalloenzyme carbonic anhydrase (CA, EC The physiologically and pharmacologically relevant human (h) isoforms hCA I and II (cytosolic isozymes), as well as the transmembr...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Angapelly S,Ramya PVS,Angeli A,Del Prete S,Capasso C,Arifuddin M,Supuran CT

    更新日期:2017-10-15 00:00:00

  • Anti-tubercular activities of 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine analogues endowed with high activity toward non-replicative Mycobacterium tuberculosis.

    abstract::Thirty three derivatives of 2-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine analogues were synthesized by molecular modification of a reported antimycobacterial molecule (GSK163574A). Compounds were evaluated in vitro against actively replicative and nutrient starved non-replicative Mycobacter...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Samala G,Brindha Devi P,Saxena S,Gunda S,Yogeeswari P,Sriram D

    更新日期:2016-11-01 00:00:00

  • Synthesis and characterization of some atypical sphingoid bases.

    abstract::Sphingolipids are ubiquitous and abundant components of all eukaryotic and some prokaryotic organisms. Sphingolipids show a large structural variety not only between the different species, but also within an individual cell. This variety is not limited to alterations in the polar headgroups of e.g. glycosphingolipids,...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Saied EM,Le TL,Hornemann T,Arenz C

    更新日期:2018-08-07 00:00:00

  • Protease inhibitors. Part 8: synthesis of potent Clostridium histolyticum collagenase inhibitors incorporating sulfonylated L-alanine hydroxamate moieties.

    abstract::A series of hydroxamates was prepared by reaction of alkyl/arylsulfonyl halides with N-2-chlorobenzyl-L-alanine, followed by conversion of the COOH moiety to the CONHOH group, with hydroxylamine in the presence of carbodiimides. Other structurally related compounds were obtained by reaction of N-2-chlorobenzyl-L-alani...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Scozzafava A,Supuran CT

    更新日期:2000-03-01 00:00:00

  • Identification of a new class of potent Cdc7 inhibitors designed by putative pharmacophore model: Synthesis and biological evaluation of 2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-ones.

    abstract::Cell division cycle 7 (Cdc7) is a serine/threonine kinase that plays important roles in the regulation of DNA replication process. A genetic study indicates that Cdc7 inhibition can induce selective tumor-cell death in a p53-dependent manner, suggesting that Cdc7 is an attractive target for the treatment of cancers. I...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Kurasawa O,Oguro Y,Miyazaki T,Homma M,Mori K,Iwai K,Hara H,Skene R,Hoffman I,Ohashi A,Yoshida S,Ishikawa T,Cho N

    更新日期:2017-04-01 00:00:00

  • Novel 5-HT7R antagonists, arylsulfonamide derivatives of (aryloxy)propyl piperidines: Add-on effect to the antidepressant activity of SSRI and DRI, and pro-cognitive profile.

    abstract::A novel series of arylsulfonamide derivatives of (aryloxy)propyl piperidines was designed to obtain potent 5-HT7R antagonists. Among the compounds evaluated herein, 3-chloro-N-{1-[3-(1,1-biphenyl-2-yloxy)2-hydroxypropyl]piperidin-4-yl}benzenesulfonamide (25) exhibited antagonistic properties at 5-HT7R and showed selec...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Canale V,Partyka A,Kurczab R,Krawczyk M,Kos T,Satała G,Kubica B,Jastrzębska-Więsek M,Wesołowska A,Bojarski AJ,Popik P,Zajdel P

    更新日期:2017-05-15 00:00:00

  • Tyrenes: synthesis of new antiproliferative compounds with an extended conjugation.

    abstract::A series of substituted styryl-acrylonitriles was designed and synthesized. The new compounds, called tyrenes, were tested for the ability to inhibit acute lymphocytic leukemia (ALL) cancer cell growth, as well as on their toxicity to normal bone marrow (NBM) cells. The results showed that 3,4-dihydroxystyryl-acryloni...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Demin P,Rounova O,Grunberger T,Cimpean L,Sharfe N,Roifman CM

    更新日期:2004-06-01 00:00:00

  • 'Carba'-carfentanil (trans isomer): a μ opioid receptor (MOR) partial agonist with a distinct binding mode.

    abstract::There is strong evidence to indicate that a positively charged nitrogen of endogenous and exogenous opioid ligands forms a salt bridge with the Asp residue in the third transmembrane helix of opioid receptors. To further examine the role of this electrostatic interaction in opioid receptor binding and activation, we s...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Weltrowska G,Lemieux C,Chung NN,Guo JJ,Wilkes BC,Schiller PW

    更新日期:2014-09-01 00:00:00

  • Synthesis and evaluation of the 2,4-diaminoquinazoline series as anti-tubercular agents.

    abstract::The 2,4-diaminoquinazoline class of compounds has previously been identified as an effective inhibitor of Mycobacterium tuberculosis growth. We conducted an extensive evaluation of the series for its potential as a lead candidate for tuberculosis drug discovery. Three segments of the representative molecule N-(4-fluor...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Odingo J,O'Malley T,Kesicki EA,Alling T,Bailey MA,Early J,Ollinger J,Dalai S,Kumar N,Singh RV,Hipskind PA,Cramer JW,Ioerger T,Sacchettini J,Vickers R,Parish T

    更新日期:2014-12-15 00:00:00

  • High affinity central benzodiazepine receptor ligands. Part 3: insights into the pharmacophore and pattern recognition study of intrinsic activities of pyrazolo[4,3-c]quinolin-3-ones.

    abstract::Novel 2-phenyl-2,5-dihydropyrazolo[4,3-c]quinolin-3-(3H)-ones (PQs) endowed with high affinity for central benzodiazepine receptor (BzR) were synthesized. In particular, 9-fluoro-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (2(2)) showed binding affinity in the subnanomolar concentration range and p...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Carotti A,Altomare C,Savini L,Chiasserini L,Pellerano C,Mascia MP,Maciocco E,Busonero F,Mameli M,Biggio G,Sanna E

    更新日期:2003-11-17 00:00:00

  • 11-Substituted 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine derivatives as novel topoisomerase I-targeting agents.

    abstract::Several 11-substituted benzo[i]phenanthridine derivatives were synthesized, and their TOP1-targeting activity and cytotoxicity were assessed. Comparative data indicate that TOP1-targeting was often the primary molecular target associated with their cytotoxicity. Several 11-aminoalkyl derivatives, 11-aminocarboxy deriv...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Feng W,Satyanarayana M,Tsai YC,Liu AA,Liu LF,LaVoie EJ

    更新日期:2008-09-15 00:00:00

  • Synthesis and in vitro activity of some epimeric 20 alpha-hydroxy, 20-oxime and aziridine pregnene derivatives as inhibitors of human 17 alpha-hydroxylase/C17,20-lyase and 5 alpha-reductase.

    abstract::Some epimeric 20-hydroxy, 20-oxime, 16 alpha, 17 alpha-, 17,20- and 20,21-aziridine derivatives of progesterone were synthesized and evaluated as inhibitors of human 17 alpha-hydroxylase/C17,20-lyase (P450(17) alpha) and 5 alpha-reductase (5 alpha-R). The reduction of 16-dehydropregenolone acetate (3a) was reinvestiga...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ling YZ,Li JS,Kato K,Liu Y,Wang X,Klus GT,Marat K,Nnane IP,Brodie AM

    更新日期:1998-10-01 00:00:00

  • 4-(Anilino)pyrrole-2-carboxamides: Novel non-steroidal/non-anilide type androgen antagonists effective upon human prostate tumor LNCaP cells with mutated nuclear androgen receptor.

    abstract::Various 4-(anilino)pyrrole-2-carboxamides were designed and synthesized as novel androgen receptor (AR) antagonists without steroidal or anilide structure, based on our strategy for developing full antagonists of nuclear receptors. Introduction of a bulky N-alkyl group, such as a cyclohexylmethyl or benzyl group, incr...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Wakabayashi K,Imai K,Miyachi H,Hashimoto Y,Tanatani A

    更新日期:2008-07-15 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


    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 characterizations of novel quinoline derivatives having mixed ligand activities at the kappa and mu receptors: Potential therapeutic efficacy against morphine dependence.

    abstract::Based on an established 3D pharmacophore, a series of quinoline derivatives were synthesized. The opioidergic properties of these compounds were determined by a competitive binding assay using (125)I-Dynorphine, (3)H-DAMGO and (125)I-DADLE for kappa, mu, and delta receptors, respectively. Results showed varying degree...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Deb I,Paira P,Hazra A,Banerjee S,Dutta PK,Mondal NB,Das S

    更新日期:2009-08-15 00:00:00

  • Factors that influence T box riboswitch efficacy and tRNA affinity.

    abstract::The T box riboswitch is an intriguing potential target for antibacterial drug discovery. Found primarily in Gram-positive bacteria, the riboswitch regulates gene expression by selectively responding to uncharged tRNA to control transcription readthrough. Polyamines and molecular crowding are known to specifically affe...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Zeng C,Zhou S,Bergmeier SC,Hines JV

    更新日期:2015-09-01 00:00:00

  • Novel FXR (farnesoid X receptor) modulators: Potential therapies for cholesterol gallstone disease.

    abstract::Metabolic disorders such as diabetes are known risk factors for developing cholesterol gallstone disease (CGD). Cholesterol gallstone disease is one of the most prevalent digestive diseases, leading to considerable financial and social burden worldwide. Ursodeoxycholic acid (UDCA) is the only bile acid drug approved b...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Yu DD,Andrali SS,Li H,Lin M,Huang W,Forman BM

    更新日期:2016-09-15 00:00:00

  • Structure-activity relationship and conformational analysis of monoglycosylceramides on the syngeneic mixed leukocyte reaction.

    abstract::We examined effects of alpha-, beta-galactosylceramides (CalCers) and alpha-, beta-glucosylceramides (GlcCers) on the syngeneic mixed leukocyte reaction (MLR) using spleen cells (responder cells) and dendritic cells (DC, stimulator cells). The DC pretreated with these alpha-monoglycosylceramides markedly stimulated th...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Iijima H,Kimura K,Sakai T,Uchimura A,Shimizu T,Ueno H,Natori T,Koezuka Y

    更新日期:1998-10-01 00:00:00

  • Structural insights into the hot spot amino acid residues of mushroom tyrosinase for the bindings of thujaplicins.

    abstract::Tyrosinase inhibitors are important agents for cosmetic products. We examined here the inhibitory effects of three isomers of thujaplicins (α, β and γ) on mushroom tyrosinase and analyzed their binding modes using a homology model from the crystal structure of Streptomyces castaneoglobisporus tyrosinase (PDB ID: 1wx2)...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Takahashi S,Kamiya T,Saeki K,Nezu T,Takeuchi S,Takasawa R,Sunaga S,Yoshimori A,Ebizuka S,Abe T,Tanuma S

    更新日期:2010-11-15 00:00:00

  • Synthesis and characterization of modified nucleotides in the 970 hairpin loop of Escherichia coli 16S ribosomal RNA.

    abstract::The synthesis of the 6-O-DPC-2-N-methylguanosine (m(2)G) nucleoside and the corresponding 5'-O-DMT-2'-O-TOM-protected 6-O-DPC-2-N-methylguanosine phosphoramidite is reported [DPC, diphenyl carbamoyl; DMT, 4,4'-dimethoxytrityl; TOM, [(triisopropylsilyl)oxy]methyl]. The availability of the phosphoramidite allows for syn...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Abeydeera ND,Chow CS

    更新日期:2009-08-15 00:00:00