当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY期刊下所有文献 > A combination of in silico and SAR studies to identify binding hot spots of Bcl-xL inhibitors.

A combination of in silico and SAR studies to identify binding hot spots of Bcl-xL inhibitors.

Abstract：

:Inhibition of Bcl-2 family protein-protein interactions (PPI) is a very promising direction in cancer chemotherapy. Hence over the last decade, many medicinal chemistry studies endeavoured to discover drug candidates, and a wealth of chemical scaffolds with striking chemical diversity was reported as Bcl-xL inhibitors. This raises the question of whether all these molecules could occupy a unique binding site, or rather discrete pockets of the protein surface. To test if small and chemically diverse Bcl-xL inhibitors are likely to bind a single pocket, and to identify which pocket, we used a battery of computational and modeling approaches. We first checked that the large dataset of Bcl-xL inhibitors we built can actually fit to a universal pharmacophore. Then we defined the probable binding hot spots of interaction through comparison of crystal structures, as well as virtual fragment screening. Finally, new analogues of small polyphenol derivatives were synthesized to precisely probe a hydrogen bond suggested by docking experiments. Bcl-xL inhibition potency of these products confirmed the predicted binding mode. This combination of X-ray structure exploration, molecular modeling studies and medicinal chemistry supports that all these small Bcl-xL inhibitors occupy the same hot spot of interaction. The identification of this binding site should help the design and optimization of small PPI Bcl-xL inhibitors.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Levoin N,Vo DD,Gautier F,Barillé-Nion S,Juin P,Tasseau O,Grée R

doi

10.1016/j.bmc.2015.02.060

subject

Has Abstract

pub_date

2015-04-15 00:00:00

pages

1747-57

issue

8

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(15)00164-9

journal_volume

23

pub_type

杂志文章

相关文献

BIOORGANIC & MEDICINAL CHEMISTRY文献大全
  • Replacement of benzylic hydroxy group by vinyl or hydroxymethyl moiety at the 3-benzazepine scaffold retaining GluN2B affinity.

    abstract：:Since overactivation of NMDA receptors is associated with neurodegenerative disorders, the design and development of subunit-selective NMDA receptor antagonists are of great interest. In order to avoid the formation of quinone-like intermediates as starting point for degradation the benzylic OH group of the lead compo...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2017.07.059

    authors： Rath S,Schepmann D,Wünsch B

    更新日期：2017-10-15 00:00:00

  • Synthesis and screening of a cyclic peptide library: discovery of small-molecule ligands against human prolactin receptor.

    abstract：:Prolactin receptor is involved in normal lactation and reproduction; however, excessive prolactin levels can cause various reproductive disorders such as prolactinomas. Small-molecule antagonists against the human prolactin receptor (hPRLr) thus have potential clinical applications and may serve as useful molecular pr...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2008.01.015

    authors： Liu T,Joo SH,Voorhees JL,Brooks CL,Pei D

    更新日期：2009-02-01 00:00:00

  • Novel designed enediynes: molecular design, chemical synthesis, mode of cycloaromatization and guanine-specific DNA cleavage.

    abstract：:The molecular design and chemical synthesis of novel enediyne molecules related to the neocarzinostatin chromophore (1), and their chemical and DNA cleaving properties are described. The 10-membered enediyne triols 16-18 were effectively synthesized from xylitol (10) in a short step, and found to be quite stable when ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/0968-0896(95)00170-0

    authors： Toshima K,Ohta K,Kano T,Nakamura T,Nakata M,Kinoshita M,Matsumura S

    更新日期：1996-01-01 00:00:00

  • Synthesis and biological evaluation of benzimidazole-5-carbohydrazide derivatives as antimalarial, cytotoxic and antitubercular agents.

    abstract：:A series of N'-substituted-2-(5-nitrofuran or 5-nitrothiophen-2-yl)-3H-benzo[d]imidazole-5-carbohydrazide derivatives were synthesized and investigated for their abilities to inhibit β-hematin formation, hemoglobin hydrolysis and in vivo for their antimalarial efficacy in rodent Plasmodium berghei. Selected analogues ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2011.01.050

    authors： Camacho J,Barazarte A,Gamboa N,Rodrigues J,Rojas R,Vaisberg A,Gilman R,Charris J

    更新日期：2011-03-15 00:00:00

  • Three new bioactive bis-adjacent THF-ring acetogenins from the bark of Annona squamosa.

    abstract：:Continuing work on the bioactivity-directed fractionation of the bark of Annona squamosa has resulted in the discovery of three new Annonaceous acetogenins, (2,4-cis and trans)-squamolinone (1), (2,4-cis and trans)-9-oxoasimicinone (2), and bullacin B (3). Compounds 1-3 are all adjacent bis-THF ring acetogenins with 2...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(98)00018-2

    authors： Hopp DC,Alali FQ,Gu ZM,McLaughlin JL

    更新日期：1998-05-01 00:00:00

  • Novel antioxidant agents deriving from molecular combinations of vitamins C and E analogues: 3,4-dihydroxy-5(R).

    abstract：:Molecular combinations of two antioxidants (i.e., ascorbic acid and the pharmacophore of alpha-tocopherol), namely the 2,3-dihydroxy-2,3-enono-1,4-lactone and the chromane residues, have been designed and tested for their radical scavenging activities. When evaluated for their capability to inhibit malondialdehyde (MD...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(00)00205-4

    authors： Manfredini S,Vertuani S,Manfredi B,Rossoni G,Calviello G,Palozza P

    更新日期：2000-12-01 00:00:00

  • Design and synthesis of de novo cytotoxic alkaloids by mimicking the bioactive conformation of paclitaxel.

    abstract：:Novel paclitaxel-mimicking alkaloids were designed and synthesized based on a bioactive conformation of paclitaxel, that is, REDOR-Taxol. The alkaloid 2 bearing a 5-7-6 tricyclic scaffold mimics REDOR-Taxol best among the compounds designed and was found to be the most potent compound against several drug-sensitive an...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2010.07.069

    authors： Sun L,Veith JM,Pera P,Bernacki RJ,Ojima I

    更新日期：2010-10-01 00:00:00

  • The effect of the length and flexibility of the side chain of basic amino acids on the binding of antimicrobial peptides to zwitterionic and anionic membrane model systems.

    abstract：:The intent of this investigation was to determine the effect of varying the side chain length of the basic amino acids residues on the binding of a series of antimicrobial peptides (AMPs) to zwitterionic and anionic LUVs, SUVs and micelles. These AMPs are based on the incorporation of three dipeptide units consisting ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2012.01.015

    authors： Russell AL,Williams BC,Spuches A,Klapper D,Srouji AH,Hicks RP

    更新日期：2012-03-01 00:00:00

  • Synthesis and muscarinic activities of 3-(pyrazolyl)-1,2,5,6-tetrahydropyridine derivatives.

    abstract：:A series of 3-(pyrazolyl)-1,2,5,6-tetrahydropyridine derivatives (B) was synthesized and tested for muscarinic activity in receptor binding assays using [3H]-oxotremorine-M (3H-OXO-M) and [3H]-pirenzepine (3H-PZ) as ligands. Potential muscarinic agonistic or antagonistic properties of the compounds were determined usi...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/0968-0896(96)00001-6

    authors： Plate R,Plaum MJ,de Boer T,Andrews JS,Rae DR,Gibson S

    更新日期：1996-02-01 00:00:00

  • Synthesis and evaluation of novel modified γ-lactam prostanoids as EP4 subtype-selective agonists.

    abstract：:To identify chemically and metabolically stable subtype-selective EP4 agonists, design and synthesis of a series of modified γ-lactam prostanoids has been continued. Prostanoids bearing 2-oxo-1,3-oxazolidine, 2-oxo-1,3-thiazolidine and 5-thioxopyrrolidine as a surrogate for the γ-hydroxycyclopentanone without a troubl...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2011.12.009

    authors： Kambe T,Maruyama T,Nagase T,Ogawa S,Minamoto C,Sakata K,Maruyama T,Nakai H,Toda M

    更新日期：2012-01-15 00:00:00

  • Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones.

    abstract：:A series of azetidin-2-ones substituted at positions 1, 3 and 4 of the azetidinone ring scaffold were synthesised and evaluated for antiproliferative, cytotoxic and tubulin-binding activity. In these compounds, the cis double bond of the vascular targeting agent combretastatin A-4 is replaced with the azetidinone ring...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2011.02.022

    authors： O'Boyle NM,Greene LM,Bergin O,Fichet JB,McCabe T,Lloyd DG,Zisterer DM,Meegan MJ

    更新日期：2011-04-01 00:00:00

  • Synthesis of (R)- or (S)-valinol using ω-transaminases in aqueous and organic media.

    abstract：:Valinol is part of numerous pharmaceuticals and has various other important applications. Optically pure valinol (ee >99%) was prepared employing different ω-transaminases from the corresponding prochiral hydroxy ketone. By the choice of the enzyme the (R)- as well as the (S)-enantiomer were accessible. Reductive amin...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2014.05.055

    authors： Fuchs CS,Simon RC,Riethorst W,Zepeck F,Kroutil W

    更新日期：2014-10-15 00:00:00

  • Structure-activity studies of cyclic ketone inhibitors of the serine protease plasmin: design, synthesis, and biological activity.

    abstract：:Three series of cyclic ketone inhibitors were synthesized and evaluated against the serine protease plasmin. Peptide inhibitors that incorporated 3-oxotetrahydrofuran and 3-oxotetrahydrothiophene 1,1-dioxide groups had the highest activities. Alkylamino substituents, which were designed to bind in the S1 subsite of pl...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2006.08.040

    authors： Xue F,Seto CT

    更新日期：2006-12-15 00:00:00

  • Enhanced RNA binding of dimerized aminoglycosides.

    abstract：:Aminoglycoside antibiotics have recently emerged as an intriguing family of RNA binding molecules and they became leading structures for the design of novel RNA ligands. The demystification of the aminoglycoside-RNA recognition phenomenon is required for the development of superior binders. To explore the existence of...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(99)00071-1

    authors： Michael K,Wang H,Tor Y

    更新日期：1999-07-01 00:00:00

  • Phenolic group on A-ring is key for dracoflavan B as a selective noncompetitive inhibitor of α-amylase.

    abstract：:A high throughput assay was applied to guide the isolation of a new pancreatic α-amylase inhibitor, dracoflavan B, from the dragon's blood resin from Daemonorops draco. Applying C18 column, we successfully isolated both diastereomers and their structures verified by (1)H NMR spectra in comparison with the literature v...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2015.11.008

    authors： Toh ZS,Wang H,Yip YM,Lu Y,Lim BJ,Zhang D,Huang D

    更新日期：2015-12-15 00:00:00

  • Synthesis and evaluation of a radioiodinated bladder cancer specific peptide.

    abstract：:Bladder cancer is the second most common cancer of the urinary tract, however the invasive cystoscopy is still the standard technique for diagnosis and surveillance of bladder cancer. Herein, we radiolabel bladder cancer specific peptide with radioactive iodine ((131/124)I) and evaluate its potential as a new radiopha...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2012.05.049

    authors： Ha YS,Lee HY,An GI,Kim J,Kwak W,Lee EJ,Lee SM,Lee BH,Kim IS,Belay T,Lee W,Ahn BC,Lee J,Yoo J

    更新日期：2012-07-15 00:00:00

  • 1,2,3,4-tetrahydroisoquinoline derivatives: a new class of 5-HT1A receptor ligands.

    abstract：:Three series of new N-substituted 1,2,3,4-tetrahydroisoquinolines with 2-, 3-, and 4-membered alkyl chains (a, b, and c, respectively) were synthesized, and the effect of some structural modifications on their 5-HT1A receptor affinities and functional properties was discussed. It was found that the volume of the termi...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(98)00238-7

    authors： Mokrosz MJ,Bojarski AJ,Duszyńska B,Tatarczyńska E,Kłodzińska A,Dereń-Wesołek A,Charakchieva-Minol S,Chojnacka-Wójcik E

    更新日期：1999-02-01 00:00:00

  • Novel steroidal vinyl fluorides as inhibitors of steroid C17(20) lyase.

    abstract：:20-fluoro-17(20)-pregnenolone derivatives were designed as enol mimics of pregnenolone. All of the targeted, novel fluoroolefins were potent inhibitors of C17(20) lyase. ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(01)00354-6

    authors： Burkhart JP,Weintraub PM,Gates CA,Resvick RJ,Vaz RJ,Friedrich D,Angelastro MR,Bey P,Peet NP

    更新日期：2002-04-01 00:00:00

  • Synthesis of both enantiomers of hydroxypipecolic acid derivatives equivalent to 5-azapyranuronic acids and evaluation of their inhibitory activities against glycosidases.

    abstract：:We have synthesized 3-hydroxy- and 3,4,5-trihydroxypipecolic acid derivatives corresponding to 5-aza derivatives of uronic acids and evaluated their inhibitory activities against various glycosidases including beta-glucuronidase. Compounds 4 and 5 were chosen as common intermediates for the synthesis of 3,4,5-trihydro...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2008.06.016

    authors： Yoshimura Y,Ohara C,Imahori T,Saito Y,Kato A,Miyauchi S,Adachi I,Takahata H

    更新日期：2008-09-01 00:00:00

  • Identification of a novel class of selective Tpl2 kinase inhibitors: 4-Alkylamino-[1,7]naphthyridine-3-carbonitriles.

    abstract：:We have previously reported the discovery and initial SAR of the [1,7]naphthyridine-3-carbonitriles and quinoline-3-carbonitriles as Tumor Progression Loci-2 (Tpl2) kinase inhibitors. In this paper, we report new SAR efforts which have led to the identification of 4-alkylamino-[1,7]naphthyridine-3-carbonitriles. These...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2007.06.054

    authors： Kaila N,Green N,Li HQ,Hu Y,Janz K,Gavrin LK,Thomason J,Tam S,Powell D,Cuozzo J,Hall JP,Telliez JB,Hsu S,Nickerson-Nutter C,Wang Q,Lin LL

    更新日期：2007-10-01 00:00:00

  • Inhibition of bovine plasma amine oxidase by 1,4-diamino-2-butenes and -2-butynes.

    abstract：:Bovine plasma amine oxidase (BPAO) was previously shown to be irreversibly inhibited by propargylamine and 2-chloroallylamine. 1,4-Diamine versions of these two compounds are here shown to be highly potent inactivators, with IC50 values near 20 microM. Mono-N-alkylation or N,N-dialkylation greatly lowered the inactiva...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(03)00521-2

    authors： Jeon HB,Lee Y,Qiao C,Huang H,Sayre LM

    更新日期：2003-10-15 00:00:00

  • Benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives as multiple inhibitors of bacterial Mur ligases (MurC-MurF).

    abstract：:Enzymes catalyzing the biosynthesis of bacterial peptidoglycan represent traditionally a collection of highly selective targets for novel antibacterial drug design. Four members of the bacterial Mur ligase family-MurC, MurD, MurE and MurF-are involved in the intracellular steps of peptidoglycan biosynthesis, catalyzin...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2014.05.058

    authors： Perdih A,Hrast M,Barreteau H,Gobec S,Wolber G,Solmajer T

    更新日期：2014-08-01 00:00:00

  • Biaryl diacid inhibitors of human s-PLA2 with anti-inflammatory activity.

    abstract：:Twenty-four hydrophobic dicarboxylic acids are described which were evaluated as inhibitors of 14 kDa human platelet phospholipase A2 (HP-PLA2). In general, biarylacetic acid derivatives were found to be more active than biaryl acids or biarylpropanoic acids. More potent inhibitors were obtained when hydrophobic group...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(00)00047-x

    authors： Springer DM,Luh BY,Bronson JJ,McElhone KE,Mansuri MM,Gregor KR,Nettleton DO,Stanley PL,Tramposch KM

    更新日期：2000-05-01 00:00:00

  • Anti-HBV and cytotoxic activities of pyranocoumarin derivatives.

    abstract：:Four natural pyranocoumarins clausenidin (1), nordentatin (2), clausarin (3), and xanthoxyletin (4) were isolated from the medicinal plant Clausena excavata. Recently, we found that 1 and 2 suppressed hepatitis B virus surface antigen in HepA2 cells, and in addition, 1-3 showed cytotoxic activity against four human ca...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2008.12.007

    authors： Su CR,Yeh SF,Liu CM,Damu AG,Kuo TH,Chiang PC,Bastow KF,Lee KH,Wu TS

    更新日期：2009-08-15 00:00:00

  • New minor taxanes analogues from the needles of Taxus canadenis.

    abstract：:Seven new taxanes were isolated from the needles of the Canadian yew: unusual functional groups, positions and/or stereochemical features are described. Their chemical structures were rigorously characterized by detailed high resolution NMR analyses and confirmed by high resolution Fast Atom Bombardment Mass Spectrome...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(02)00347-4

    authors： Shi QW,Sauriol F,Mamer O,Zamir LO

    更新日期：2003-01-17 00:00:00

  • The conformation and activity relationship of fused analogs of DuP753.

    abstract：:We have prepared three conformationally restricted analogs of DuP753 in which one of the phenyl rings in the biphenyl moiety is fused to the imidazole ring, and have investigated the conformation-biological activity relationship of these compounds. Conformational analysis on DuP753 and these compounds confirms that a ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/0968-0896(95)00002-x

    authors： Yoo SE,Shin YA,Lee SH,Kim NJ

    更新日期：1995-03-01 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

  • 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

    doi：10.1016/j.bmc.2008.08.018

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

    更新日期：2008-09-15 00:00:00

  • 000Synthesis of new α-aminophosphonates: Evaluation as anti-inflammatory agents and QSAR studies.

    abstract：:In this paper, we report the synthesis of a new series of α-aminophosphonates derivatives based in an efficient three-component reaction. All compounds prepared showed significant anti-inflammatory activity, being the compounds 1a, 1c, 1d, 1f, 2b and 2c the most promising ones, in terms of maximal efficacy (over 95%),...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2018.12.041

    authors： Romero-Estudillo I,Viveros-Ceballos JL,Cazares-Carreño O,González-Morales A,de Jesús BF,López-Castillo M,Razo-Hernández RS,Castañeda-Corral G,Ordóñez M

    更新日期：2019-06-15 00:00:00

  • Optimization and determination of the absolute configuration of a series of potent inhibitors of human papillomavirus type-11 E1-E2 protein-protein interaction: a combined medicinal chemistry, NMR and computational chemistry approach.

    abstract：:We have previously reported the discovery and initial SAR optimization of the first series of inhibitors of the human papillomavirus type-11 (HPV11) E1-E2 protein-protein interaction. These inhibitors featured an indandione system spiro-fused onto an all syn substituted tetrahydrofuran ring. In this paper, we report n...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2007.01.036

    authors： Goudreau N,Cameron DR,Déziel R,Haché B,Jakalian A,Malenfant E,Naud J,Ogilvie WW,O'meara J,White PW,Yoakim C

    更新日期：2007-04-01 00:00:00