当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Computational methods-guided design of modulators targeting protein-protein interactions (PPIs).

Computational methods-guided design of modulators targeting protein-protein interactions (PPIs).

Abstract：

:Protein-protein interactions (PPIs) play a pivotal role in extensive biological processes and are thus crucial to human health and the development of disease states. Due to their critical implications, PPIs have been spotlighted as promising drug targets of broad-spectrum therapeutic interests. However, owing to the general properties of PPIs, such as flat surfaces, featureless conformations, difficult topologies, and shallow pockets, previous attempts were faced with serious obstacles when targeting PPIs and almost portrayed them as "intractable" for decades. To date, rapid progress in computational chemistry and structural biology methods has promoted the exploitation of PPIs in drug discovery. These techniques boost their cost-effective and high-throughput traits, and enable the study of dynamic PPI interfaces. Thus, computational methods represent an alternative strategy to target "undruggable" PPI interfaces and have attracted intense pharmaceutical interest in recent years, as exemplified by the accumulating number of successful cases. In this review, we first introduce a diverse set of computational methods used to design PPI modulators. Herein, we focus on the recent progress in computational strategies and provide a comprehensive overview covering various methodologies. Importantly, a list of recently-reported successful examples is highlighted to verify the feasibility of these computational approaches. Finally, we conclude the general role of computational methods in targeting PPIs, and also discuss future perspectives on the development of such aids.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Qiu Y,Li X,He X,Pu J,Zhang J,Lu S

doi

10.1016/j.ejmech.2020.112764

subject

Has Abstract

pub_date

2020-12-01 00:00:00

pages

112764

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(20)30736-4

journal_volume

207

pub_type

杂志文章,评审

相关文献

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • In vitro and in vivo biological evaluation of new 4,5-disubstituted 1,2,3-triazoles as cis-constrained analogs of combretastatin A4.

    abstract：:To find new and better antivascular agents for cancer therapy, a series of combretastatin A4 (CA4) analogs were prepared from 1,3-diaryl-2-nitroprop-1-enes (6-12) obtained in a two-step synthesis from appropriate arylaldehydes and 2-aryl-1-nitroethanes (4 or 5). Treatment of these 1,3-diaryl-2-nitroprop-1-enes 6-12 by...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2012.04.017

    authors： Mur Blanch N,Chabot GG,Quentin L,Scherman D,Bourg S,Dauzonne D

    更新日期：2012-08-01 00:00:00

  • 5-Ene-4-thiazolidinones induce apoptosis in mammalian leukemia cells.

    abstract：:The article presents the synthesis of 5-ene-4-thiazolidinone derivatives with pyrazole core linked by enamine group. The structure and purity of compounds were confirmed by analytical and spectral data including X-ray analysis. Target compounds were screened for their anticancer activity and selective antileukemic act...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2016.03.089

    authors： Senkiv J,Finiuk N,Kaminskyy D,Havrylyuk D,Wojtyra M,Kril I,Gzella A,Stoika R,Lesyk R

    更新日期：2016-07-19 00:00:00

  • One-pot microwave assisted synthesis of new 2-alkoxycarbonylmethylene-4-oxo-1,5-benzo-, naphtho-, and pyridodiazepines and assessment of their cytogenetic activity.

    abstract：:1,5-Benzo-, naphtho-, and pyridodiazepines 3 have been synthesized in excellent yields in one-step from the reaction of o-phenylenediamines with acetonedicarboxylates through microwave assisted acid catalysis. In order to ascertain their cytogenetic activity in vitro at doses equivalent to the per os doses of common 1...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2013.06.028

    authors： Eleftheriadis N,Neochoritis CG,Tsoleridis CA,Stephanidou-Stephanatou J,Iakovidou-Kritsi Z

    更新日期：2013-09-01 00:00:00

  • New amphiphilic neamine conjugates bearing a metal binding motif active against MDR E. aerogenes Gram-negative bacteria.

    abstract：:Structure of bacterial envelope is one of the major factors contributing to Gram negative bacterial resistance. To develop new agents that target the bacterial membranes, we synthesized, by analogy with our previous peptide conjugates, new amphiphilic 3',4',6-trinaphthylmethylene neamines functionalized at position 5 ...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2016.10.054

    authors： Allam A,Maigre L,Alves de Sousa R,Dumont E,Vergalli J,Pagès JM,Artaud I

    更新日期：2017-02-15 00:00:00

  • Discovery and optimization of adamantane carboxylic acid derivatives as potent diacylglycerol acyltransferase 1 inhibitors for the potential treatment of obesity and diabetes.

    abstract：:We have developed a series of adamantane carboxylic acid derivatives exhibiting potent diacylglycerol acyltransferase 1 (DGAT1) inhibitory activities. Optimization of the series led to the discovery of E-adamantane carboxylic acid compound 43c, which showed excellent in vitro activity with an IC50 value of 5 nM agains...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2015.06.043

    authors： Pagire SH,Pagire HS,Lee GB,Han SJ,Kwak HJ,Kim JY,Kim KY,Rhee SD,Ryu JI,Song JS,Bae MA,Park MJ,Kim D,Lee DH,Ahn JH

    更新日期：2015-08-28 00:00:00

  • Design, synthesis and antitubercular evaluation of novel series of N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives.

    abstract：:The analogs of N-[4-(piperazin-1-yl)phenyl]cinnamamide were designed and synthesized by molecular hybridization approach in which part C of the designed molecule was linked through amide and carbamate functionality that improves the physicochemical properties and govern the pharmacokinetic and pharmacodynamic behavior...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2014.01.024

    authors： Patel KN,Telvekar VN

    更新日期：2014-03-21 00:00:00

  • N-Aryl-N'-(chroman-4-yl)ureas and thioureas display in vitro anticancer activity and selectivity on apoptosis-resistant glioblastoma cells: screening, synthesis of simplified derivatives, and structure-activity relationship analysis.

    abstract：:A series of chroman derivatives previously reported as potassium channel openers, as well as some newly synthesized simplified structures, were examined for their in vitro effects on the growth of three human high-grade glioma cell lines: U373, T98G, and Hs683. Significant in vitro growth inhibitory activity was obser...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2012.06.050

    authors： Goffin E,Lamoral-Theys D,Tajeddine N,de Tullio P,Mondin L,Lefranc F,Gailly P,Rogister B,Kiss R,Pirotte B

    更新日期：2012-08-01 00:00:00

  • Synthesis and antiproliferative activity of novel selenoester derivatives.

    abstract：:A series of 31 new selenoesters were synthesized and their cytotoxic activity was evaluated against a prostate cancer cell line (PC-3). The most active compounds were also tested against three tumoural cell lines (MCF-7, A-549 and HT-29) and one non-tumour prostate cell line (RWPE-1). Thirteen compounds showed signifi...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2013.11.034

    authors： Domínguez-Álvarez E,Plano D,Font M,Calvo A,Prior C,Jacob C,Palop JA,Sanmartín C

    更新日期：2014-02-12 00:00:00

  • Polycyclic propargylamine and acetylene derivatives as multifunctional neuroprotective agents.

    abstract：:The aim of this study was to design drug-like molecules with multiple neuroprotective mechanisms which would ultimately inhibit N-methyl-D-aspartate (NMDA) receptors, block L-type voltage gated calcium channels (VGCC) and inhibit apoptotic processes as well as the monoamine oxidase-B (MAO-B) enzyme in the central nerv...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2014.04.039

    authors： Zindo FT,Barber QR,Joubert J,Bergh JJ,Petzer JP,Malan SF

    更新日期：2014-06-10 00:00:00

  • A phosphonamidate containing aromatic N-terminal amino group as inhibitor of leucine aminopeptidase-design, synthesis and stability.

    abstract：:Fully deprotected phosphonamidate dipeptides, predicted as effective inhibitors of cytosolic leucine aminopeptidase, showed unexpected instability in water solution at pH below 12. Their hydrolysis rate was strictly correlated with basicity of the N-terminal amino group. To improve this feature a phosphonamidate analo...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2006.03.023

    authors： Mucha A,Kunert A,Grembecka J,Pawełczak M,Kafarski P

    更新日期：2006-06-01 00:00:00

  • Synthesis of substituted 3-amino-N-phenyl-1H-indazole-1-carboxamides endowed with antiproliferative activity.

    abstract：:Several new N-phenyl-1H-indazole-1-carboxamides 1c-h and 4l,m were prepared by reacting phenyl isocyanate derivatives 3a,b with 3-amino-1H-indazole derivatives 2c,e,g or 1H-indazole 2l respectively. Chemical transformations of compounds 1a,b and 1g,h gave 3-acetamido-N-phenyl-1H-indazole-1-carboxamide derivatives 5a,b...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2010.10.032

    authors： Maggio B,Raimondi MV,Raffa D,Plescia F,Cascioferro S,Plescia S,Tolomeo M,Di Cristina A,Pipitone RM,Grimaudo S,Daidone G

    更新日期：2011-01-01 00:00:00

  • 2,2'-bipyridyl based copper complexes down regulate expression of pro-inflammatory cytokines and suppress MAPKs in mitogen induced Peripheral blood mononuclear cells.

    abstract：:2,2'-bipyridyl based copper complex I: [CuC24H22N6O10] at 10 nM and complex Ia: [Cu2C32H43N8O3](PF6)4 at 7 nM exhibited 50% inhibition of lymphocyte proliferation and less than 20% cytotoxicity in peripheral blood mononuclear cells (PBMCs). Further, pro-inflammatory cytokines such as TNF-alpha and IL-1beta and pro-inf...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2010.01.041

    authors： Rupesh KR,Priya AM,Sundarakrishnan B,Venkatesan R,Lakshmi BS,Jayachandran S

    更新日期：2010-06-01 00:00:00

  • The chemical diversity and structure-based evolution of non-peptide CXCR4 antagonists with diverse therapeutic potential.

    abstract：:The CXC chemokine receptor 4 (CXCR4) is a highly reserved G-protein coupled 7-transmembrane (TM) chemokine receptor which consists of 352 amino acids. CXCR4 has only one endogenous chemokine ligand of CXCL12, besides several other natural nonchemokine ligands such as extracellular ubiquitin and noncognate ligand of MI...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1016/j.ejmech.2018.02.043

    authors： Peng D,Cao B,Zhou YJ,Long YQ

    更新日期：2018-04-10 00:00:00

  • Fluoroquinolone derivatives and their anti-tubercular activities.

    abstract：:Tuberculosis (TB) remains one of the most widespread and leading deadliest diseases, around one-third of the world's population harbor a latent infection by Mycobacterium tuberculosis (MTB), and 5-10% eventually develop an active TB. The emergency of MTB new virulent forms as well as the co-infection between MTB and H...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1016/j.ejmech.2018.01.080

    authors： Fan YL,Wu JB,Cheng XW,Zhang FZ,Feng LS

    更新日期：2018-02-25 00:00:00

  • Synthesis and biological evaluation of 1-(4'-Indolyl and 6'-Quinolinyl) indoles as a new class of potent anticancer agents.

    abstract：:A novel series of the biheterocycles-based compounds with core structure distinguished from combretastatin A-4 (1) and colchicine (5) have been synthesized and evaluated as potent anti-mitotic agents. Compound 1-(4'-Indolyl and 6'-quinolinyl)-4,5,6-trimethoxyindoles 13 and 19 showed substantial anti-proliferative acti...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2011.04.065

    authors： Lai MJ,Chang JY,Lee HY,Kuo CC,Lin MH,Hsieh HP,Chang CY,Wu JS,Wu SY,Shey KS,Liou JP

    更新日期：2011-09-01 00:00:00

  • Design, synthesis and antifungal activities of novel pyrrole alkaloid analogs.

    abstract：:A series of novel analogs of pyrrole alkaloid were designed and synthesized by a facile method and their structures were characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). The structure of compound 2a was identified by 2D NMR including heteronuclear multiple-quantum coherence (HMQC), hetero...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2011.01.031

    authors： Wang MZ,Xu H,Liu TW,Feng Q,Yu SJ,Wang SH,Li ZM

    更新日期：2011-05-01 00:00:00

  • Synthesis and biological evaluation of a new series of 2-amino-3-aroyl thiophene derivatives as agonist allosteric modulators of the A1 adenosine receptor. A position-dependent effect study.

    abstract：:The 2-amino-3-(p-chlorobenzoyl)thiophene scaffold has been widely employed as a pharmacophore for the identification of small molecules acting as allosteric modulators at the adenosine A1 receptor. A new series of 2-amino-3-(p-chlorobenzoyl)-4-benzyl-5-arylthiophene derivatives, characterized by the absence as well as...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2015.06.041

    authors： Romagnoli R,Baraldi PG,Lopez-Cara C,Cruz-Lopez O,Moorman AR,Massink A,IJzerman AP,Vincenzi F,Borea PA,Varani K

    更新日期：2015-08-28 00:00:00

  • Synthesis and biological screening of some novel amidocarbamate derivatives of ketoprofen.

    abstract：:A series of novel ketoprofen derivatives 4a-j bearing both amide and carbamate functionalities were prepared using benzotriazole. Selective reduction of ketoprofen produced hydroxy derivative 2, which reacts with one or 2 mol of 1-benzotriazole carboxylic acid chloride (1) gave benzotriazole derivatives 3a and 3b resp...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章,收录出版

    doi：10.1016/j.ejmech.2010.04.008

    authors： Sahoo PK,Behera P

    更新日期：2010-07-01 00:00:00

  • Identification of novel aminothiazole and aminothiadiazole conjugated cyanopyridines as selective CHK1 inhibitors.

    abstract：:Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential anti-tumor agents. Novel series of cyanopyridyl-aminothiadiazoles (synthesized from reaction of 1-(3-cyano-4,6-diphenylpyridin-2-yl)-3-phenylthiourea (14) with hydrazonoyl halides) and cyanopyridyl-aminothiazolyl-thiadiazoles (synthesized fr...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章,收录出版

    doi：10.1016/j.ejmech.2015.01.019

    authors： Gomha SM,Abdulla MM,Abou-Seri SM

    更新日期：2015-03-06 00:00:00

  • Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors.

    abstract：:In the last decades, inhibitors of histone deacetylases (HDAC) have become an important class of anti-cancer agents. In a previous study we described the synthesis of spiro[chromane-2,4'-piperidine]hydroxamic acid derivatives able to inhibit histone deacetylase enzymes. Herein, we present our exploration for new deriv...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2015.11.010

    authors： Thaler F,Moretti L,Amici R,Abate A,Colombo A,Carenzi G,Fulco MC,Boggio R,Dondio G,Gagliardi S,Minucci S,Sartori L,Varasi M,Mercurio C

    更新日期：2016-01-27 00:00:00

  • Combined inhibition of the EGFR/AKT pathways by a novel conjugate of quinazoline with isothiocyanate.

    abstract：:Epidermal growth factor receptor inhibitors (EGFR-TKIs) represent a class of compounds widely used in anticancer therapy. An increasing number of studies reports on combination therapies in which the block of the EGFR-TK activity is associated with inhibition of its downstream pathways, as PI3K-Akt. Sulforaphane targe...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2016.04.002

    authors： Tarozzi A,Marchetti C,Nicolini B,D'Amico M,Ticchi N,Pruccoli L,Tumiatti V,Simoni E,Lodola A,Mor M,Milelli A,Minarini A

    更新日期：2016-07-19 00:00:00

  • Development of novel 4-aminopyridine derivatives as potential treatments for neurological injury and disease.

    abstract：:The amine position of the K+ channel blocker 4-aminopyridine was functionalized to form amide, carbamate and urea derivatives in an attempt to identify novel compounds which restore conduction in injured spinal cord. Eight derivatives were tested in vitro, using a double sucrose gap chamber, for the ability to restore...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2005.04.017

    authors： Smith DT,Shi R,Borgens RB,McBride JM,Jackson K,Byrn SR

    更新日期：2005-09-01 00:00:00

  • Donepezil-like multifunctional agents: Design, synthesis, molecular modeling and biological evaluation.

    abstract：:Currently available drugs against Alzheimer's disease (AD) are only able to ameliorate the disease symptoms resulting in a moderate improvement in memory and cognitive function without any efficacy in preventing and inhibiting the progression of the pathology. In an effort to obtain disease-modifying anti-Alzheimer's ...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2015.10.001

    authors： Wu MY,Esteban G,Brogi S,Shionoya M,Wang L,Campiani G,Unzeta M,Inokuchi T,Butini S,Marco-Contelles J

    更新日期：2016-10-04 00:00:00

  • Para-sulfonatocalix[n]arene-based biomaterials: Recent progress in pharmaceutical and biological applications.

    abstract：:The history, properties, and characteristics of para-sulfonato-calixarenes are described. On the one hand, the inherent antibacterial and antifungal properties against microorganisms, and on the other hand non-toxicity of these supramolecules toward human organs are analyzed. The resulting biocompatibility of para-sul...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1016/j.ejmech.2020.112121

    authors： Bahojb Noruzi E,Molaparast M,Zarei M,Shaabani B,Kariminezhad Z,Ebadi B,Shafiei-Irannejad V,Rahimi M,Pietrasik J

    更新日期：2020-03-15 00:00:00

  • Optimal linker length for small molecule PROTACs that selectively target p38α and p38β for degradation.

    abstract：:We report the design of hetero-bifunctional small molecules that selectively target p38α and p38β for degradation. These proteolysis targeted chimeras (PROTACs) are based on an ATP competitive inhibitor of p38α and p38β, which is linked to thalidomide analogues to recruit the Cereblon E3 ubiquitin ligase complex. Comp...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2020.112451

    authors： Donoghue C,Cubillos-Rojas M,Gutierrez-Prat N,Sanchez-Zarzalejo C,Verdaguer X,Riera A,Nebreda AR

    更新日期：2020-09-01 00:00:00

  • Synthesis and biological evaluation of phosphorylated flavonoids as potent and selective inhibitors of cholesterol esterase.

    abstract：:A series of phosphorylated flavonoids were synthesized and investigated in vitro as inhibitors of pancreatic cholesterol esterase (CEase) and acetylcholinesterase (AChE). The results showed that most of the synthesized compounds exhibited nanomolar potency against CEase, much better than the parent flavonoids. Further...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2013.03.025

    authors： Wei Y,Peng AY,Wang B,Ma L,Peng G,Du Y,Tang J

    更新日期：2014-03-03 00:00:00

  • Asymmetric 1,5-diarylpenta-1,4-dien-3-ones: Antiproliferative activity in prostate epithelial cell models and pharmacokinetic studies.

    abstract：:To further engineer dienones with optimal combinations of potency and bioavailability, thirty-four asymmetric 1,5-diarylpenta-1,4-dien-3-ones (25-58) have been designed and synthesized for the evaluation of their in vitro anti-proliferative activity in three human prostate cancer cell lines and one non-neoplastic pros...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2017.05.062

    authors： Zhang X,Guo S,Chen C,Perez GR,Zhang C,Patanapongpibul M,Subrahmanyam N,Wang R,Keith J,Chen G,Dong Y,Zhang Q,Zhong Q,Zheng S,Wang G,Chen QH

    更新日期：2017-09-08 00:00:00

  • Synthesis, molecular modeling and biological evaluation of 2-(benzylthio)-5-aryloxadiazole derivatives as anti-tumor agents.

    abstract：:A series of 2-(benzylthio)-5-aryloxadiazole derivatives have been designed and synthesized, and their biological activities are also evaluated for EGFR inhibitory activity. Fourteen compounds among the twenty compounds are reported for the first time. Their chemical structures are characterized by (1)H NMR, MS, and el...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2011.11.015

    authors： Liu K,Lu X,Zhang HJ,Sun J,Zhu HL

    更新日期：2012-01-01 00:00:00

  • New glycosidic derivatives of histidine-containing dipeptides with antioxidant properties and resistant to carnosinase activity.

    abstract：:Synthesis, antioxidant properties and resistance to carnosinase hydrolysis of histidine-containing dipeptides are reported in this study. Carnosine (beta-alanyl-l-histidine), homocarnosine (gamma-aminobutyryl-l-histidine) and anserine (beta-alanyl-3-methyl-l-histidine) were covalently derivatized with beta-cyclodextri...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2007.03.038

    authors： Bellia F,Amorini AM,La Mendola D,Vecchio G,Tavazzi B,Giardina B,Di Pietro V,Lazzarino G,Rizzarelli E

    更新日期：2008-02-01 00:00:00

  • Covalent and noncovalent constraints yield a figure eight-like conformation of a peptide inhibiting the menin-MLL interaction.

    abstract：:The interaction between menin and mixed lineage leukemia (MLL) was identified as an interesting target for treating some cancers including acute leukemia. On the basis of the known crystal structure of the MBM1-menin complex (MBM - menin binding motif), several cyclic peptides were designed. Elaboration of the effecti...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2020.112748

    authors： Fortuna P,Linhares BM,Purohit T,Pollock J,Cierpicki T,Grembecka J,Berlicki Ł

    更新日期：2020-12-01 00:00:00