当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY LETTERS期刊下所有文献 > The thermodynamic basis for the use of lipophilic efficiency (LipE) in enthalpic optimizations.

The thermodynamic basis for the use of lipophilic efficiency (LipE) in enthalpic optimizations.

Abstract：

:Approaches to improve the efficiency of molecular optimizations have received great attention and numerous efficiency metrics have been introduced to assist in this effort. Optimization of properties is equally important to optimization of potency and therefore these metrics contain potency versus property calculations. Widespread use of a metric does not guarantee its accuracy and a further understanding of which, if any, metric increases the probability of success was sought. An analysis of LE, LELP and LipE based on theoretical and experimental data was performed demonstrating that LipE most strongly correlates with compound quality as defined by enthalpy-driven binding. The basis for the prioritization of LipE over other metrics in enthalpic optimizations is described.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Shultz MD

doi

10.1016/j.bmcl.2013.08.030

subject

Has Abstract

pub_date

2013-11-01 00:00:00

pages

5992-6000

issue

21

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(13)00959-1

journal_volume

23

pub_type

杂志文章

相关文献

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS文献大全
  • Muscarinic acetylcholine receptor binding affinities of pethidine analogs.

    abstract：:A series of pethidine analogs were synthesized and their affinities for the [(3)H]N-methyl-scopolamine (NMS) binding site on muscarinic acetylcholine receptors (mAChRs) were determined using M1, M3 or M5 human mAChRs expressed by Chinese hamster ovary (CHO) cell membranes. Compound 6b showed the highest binding affini...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2015.10.029

    authors： Lee NR,Zhang X,Darna M,Dwoskin LP,Zheng G

    更新日期：2015-11-15 00:00:00

  • Synthesis and evaluation of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-aminopropanamide as human cannabinoid-1 receptor (CB1R) inverse agonists.

    abstract：:Obesity is a chronic medical condition that is affecting large population throughout the world. CB1 as a target for treatment of obesity has been under intensive studies. Taranabant was discovered and then developed by Merck as the 1st generation CB1R inverse agonist. Reported here is part of our effort on the 2nd gen...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.07.046

    authors： Du W,Jewell JP,Lin LS,Colandrea VJ,Xiao JC,Lao J,Shen CP,Bateman TJ,Reddy VB,Ha SN,Shah SK,Fong TM,Hale JJ,Hagmann WK

    更新日期：2009-09-01 00:00:00

  • Selective heterocyclic amidine inhibitors of human inducible nitric oxide synthase.

    abstract：:The potency and selectivity of a series of 5-hetero-2-iminohexahydroazepines were examined as inhibitors of the three human NOS isoforms. The effect of ring substitution of the 5-carbon for a heteroatom is presented. Potencies (IC(50)'s) for these inhibitors are in the low micromolar range for hi-NOS with some example...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(01)00523-6

    authors： Moormann AE,Metz S,Toth MV,Moore WM,Jerome G,Kornmeier C,Manning P,Hansen DW Jr,Pitzele BS,Webber RK

    更新日期：2001-10-08 00:00:00

  • Discovery of a novel 2,3-dimethylimidazo[1,2-a]pyrazine-6-carboxamide M4 positive allosteric modulator (PAM) chemotype.

    abstract：:This Letter details our efforts to discover structurally unique M4 PAMs containing 5,6-heteroaryl ring systems. In an attempt to improve the DMPK profiles of the 2,3-dimethyl-2H-indazole-5-carboxamide and 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide cores, we investigated a plethora of core replacements. This exe...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2019.126812

    authors： Temple KJ,Engers JL,Long MF,Watson KJ,Chang S,Luscombe VB,Jenkins MT,Rodriguez AL,Niswender CM,Bridges TM,Conn PJ,Engers DW,Lindsley CW

    更新日期：2020-02-01 00:00:00

  • A theoretical investigation on DPPH radical-scavenging mechanism of edaravone.

    abstract：:The mechanism of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) to scavenge DPPH radical is clarified by density functional theory (DFT) calculations. It is revealed that H-atom-abstraction rather than electron-transfer reaction is involved in the radical-scavenging process of edaravone, and H-atom at position 4 is r...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2003.07.016

    authors： Wang LF,Zhang HY

    更新日期：2003-11-03 00:00:00

  • Lead optimization of 4-(dimethylamino)quinazolines, potent and selective antagonists for the melanin-concentrating hormone receptor 1.

    abstract：:The optimization of a series of 4-(dimethylamino)quinazoline antagonists of the melanin-concentrating hormone receptor 1 (MCH-R1) is described. The combination of the elaboration of both the linker portion and the terminal phenyl ring provided N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorob...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2005.05.121

    authors： Kanuma K,Omodera K,Nishiguchi M,Funakoshi T,Chaki S,Semple G,Tran TA,Kramer B,Hsu D,Casper M,Thomsen B,Sekiguchi Y

    更新日期：2005-09-01 00:00:00

  • Conformational study of a highly specific CXCR4 inhibitor, T140, disclosing the close proximity of its intrinsic pharmacophores associated with strong anti-HIV activity.

    abstract：:We report the solution structure of T140, a truncated polyphemusin peptide analogue that efficiently inhibits infection of target cells by T-cell line-tropic strains of HIV-1 through its specific binding to a chemokine receptor, CXCR4. Nuclear magnetic resonance analysis and molecular dynamic calculations revealed tha...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(00)00664-8

    authors： Tamamura H,Sugioka M,Odagaki Y,Omagari A,Kan Y,Oishi S,Nakashima H,Yamamoto N,Peiper SC,Hamanaka N,Otaka A,Fujii N

    更新日期：2001-02-12 00:00:00

  • Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway.

    abstract：:Nrf2 is the major transcription factor that regulates many of the cytoprotective enzymes involved in the adaptive stress response. Modulation of Nrf2 could be therapeutically useful in a number of disease states. Activation can occur through either an electrophilic or non-electrophilic mechanism. To date, most of the ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章,评审

    doi：10.1016/j.bmcl.2015.04.019

    authors： Richardson BG,Jain AD,Speltz TE,Moore TW

    更新日期：2015-06-01 00:00:00

  • Discovery of thioether-bridged cyclic pentapeptides binding to Grb2-SH2 domain with high affinity.

    abstract：:Blocking the interaction between phosphotyrosine (pTyr)-containing activated receptors and the Src homology 2 (SH2) domain of the growth factor receptor-bound protein 2 (Grb 2) is considered to be an effective and non-cytotoxic strategy to develop new anti-proliferate agents due to its potential to shut down the Ras a...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.03.134

    authors： Jiang S,Liao C,Bindu L,Yin B,Worthy KW,Fisher RJ,Burke TR Jr,Nicklaus MC,Roller PP

    更新日期：2009-05-15 00:00:00

  • Investigations of the esterase, phosphatase, and sulfatase activities of the cytosolic mammalian carbonic anhydrase isoforms I, II, and XIII with 4-nitrophenyl esters as substrates.

    abstract：:The esterase, phosphatase, and sulfatase activities of carbonic anhydrase (CA, EC 4.2.1.1) isozymes, CA I, II, and XIII with 4-nitrophenyl esters as substrates was investigated. These enzymes show esterase activity with 4-nitrophenyl acetate as substrate, with second order rate constants in the range of 753-7706M(-1)s...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2008.03.012

    authors： Innocenti A,Scozzafava A,Parkkila S,Puccetti L,De Simone G,Supuran CT

    更新日期：2008-04-01 00:00:00

  • Synthesis, thermal stability, antimalarial activity of symmetrically and asymmetrically substituted tetraoxanes.

    abstract：:Symmetrically and asymmetrically substituted 1,2,4,5-tetraoxanes were synthesized by the oxidative system H(2)O(2)/TFE in presence of MeReO(3) as a catalyst. All of the synthesized compounds were characterized spectroscopically, and evaluated for cytotoxicity, and antimalarial activity. Several of these tetraoxanes ex...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2007.12.069

    authors： Atheaya H,Khan SI,Mamgain R,Rawat DS

    更新日期：2008-02-15 00:00:00

  • Identification of benzofuran central cores for the inhibition of leukotriene A(4) hydrolase.

    abstract：:Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthe...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2012.11.074

    authors： Eccles W,Blevitt JM,Booker JN,Chrovian CC,Crawford S,de Leon AR,Deng X,Fourie AM,Grice CA,Herman K,Karlsson L,Kearney AM,Lee-Dutra A,Liang J,Luna R,Pippel D,Rao N,Riley JP,Santillán A,Savall B,Tanis VM,Xue X,Y

    更新日期：2013-02-01 00:00:00

  • An alternative to Western blot analysis using RNA aptamer-functionalized quantum dots.

    abstract：:To make full use both of optical properties of quantum dots (QDs) and of specific interactions between aptamers and their ligands of interest, we employed QD-conjugated RNA aptamer interactions with histidine tag. QDs offer revolutionary fluorescence performance due to their long-term photostability, brilliant colors,...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.04.040

    authors： Shin S,Kim IH,Kang W,Yang JK,Hah SS

    更新日期：2010-06-01 00:00:00

  • Synthesis, crystal structures, molecular docking, and in vitro biological activities of transition metals with 4-(2,3-dichlorophenyl)piperazine-1-carboxylic acid.

    abstract：:Four novel mononuclear complexes, [Cd(L)2·2H2O] (1), [Ni(L)2·2H2O] (2) [Cu(L)2·H2O] (3), and [Zn(L)2·2H2O] (4) (CCDC numbers: 1444630-1444633 for complexes 1-4) (HL=4-(2,3-dichlorophenyl)piperazine-1-carboxylic acid) were synthesized, and have been characterized by IR spectroscopy, elemental analysis, and X-ray crysta...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2016.05.051

    authors： Yang DD,Chen YN,Wu YS,Wang R,Chen ZJ,Qin J,Qian SS,Zhu HL

    更新日期：2016-07-15 00:00:00

  • Discovery and optimization of potent broad-spectrum arenavirus inhibitors derived from benzimidazole and related heterocycles.

    abstract：:A series of potent arenavirus inhibitors sharing a benzimidazole core were previously reported by our group. SAR studies were expanded beyond the previous analysis, which involved the attached phenyl rings and methylamino linker portion, to include modifications focused on the benzimidazole core. These changes include...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2012.11.093

    authors： Burgeson JR,Moore AL,Gharaibeh DN,Larson RA,Cerruti NR,Amberg SM,Hruby DE,Dai D

    更新日期：2013-02-01 00:00:00

  • N-alkyl-4-[(8-azabicyclo[3.2.1]-oct-3-ylidene)phenylmethyl]benzamides, micro and delta opioid agonists: a micro address.

    abstract：:The tertiary amide delta opioid agonist 2 is a potent antinociceptive agent. Compound 2 was metabolized in vitro and in vivo to secondary amide 3, a potent and selective micro opioid agonist. The SAR of a series of N-alkyl-4-[(8-azabicyclo[3.2.1]-oct-3-ylidene)phenylmethyl]benzamides was examined. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2004.02.052

    authors： Carson JR,Coats SJ,Codd EE,Dax SL,Lee J,Martinez RP,McKown LA,Anne Neilson L,Pitis PM,Wu WN,Zhang SP

    更新日期：2004-05-03 00:00:00

  • Quinolizidinyl derivatives of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one as ligands for muscarinic receptors.

    abstract：:Quinolizidinyl derivatives of the tricyclic systems characterizing pirenzepine and nuvenzepine, were prepared and tested as ligands for muscarinic M1, M2 and M3 receptors; 5,11-dihydro-11-[(S-lupinyl)-thioacetyl]-6H-pyrido[2,3-b][1, 4]benzodiazepin-6-one exhibited IC50 = 10 nM for M1 and 760 nM for both M2 and M3 subt...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(99)00528-4

    authors： Novelli F,Sparatore A,Tasso B,Sparatore F

    更新日期：1999-10-18 00:00:00

  • The synthesis and biological evaluation of dopamine transporter inhibiting activity of substituted diphenylmethoxypiperidines.

    abstract：:The synthesis of potent 4-aryl methoxypiperidinol inhibitors of the dopamine transporter is described. Symmetrical para substituents of the benzene rings are important for high potency in binding to the dopamine transporter. 4-[Bis(4-fluorophenyl) methoxy]-1-methylpiperidine has an IC50 of 22.1+/-5.73 nM and increases...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2005.08.028

    authors： Lapa GB,Byrd GD,Lapa AA,Budygin EA,Childers SR,Jones SR,Harp JJ

    更新日期：2005-11-15 00:00:00

  • In vivo incorporation of an alkyne into proteins in Escherichia coli.

    abstract：:Using a genetic selection we identified mutants of the M. janaschii tyrosyl-tRNA synthetase that selectively charge an amber suppressor tRNA with para-propargyloxyphenylalanine in Escherichia coli. These evolved tRNA-synthetase pairs were used to site-specifically incorporate an alkynyl group into a protein, which was...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2004.12.065

    authors： Deiters A,Schultz PG

    更新日期：2005-03-01 00:00:00

  • Discovery and optimization of a series of liver X receptor antagonists.

    abstract：:The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/β) ligands. Herein we...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2012.07.048

    authors： Jiao X,Kopecky DJ,Fisher B,Piper DE,Labelle M,McKendry S,Harrison M,Jones S,Jaen J,Shiau AK,Escaron P,Danao J,Chai A,Coward P,Kayser F

    更新日期：2012-09-15 00:00:00

  • Recent advances in peptidomimetics antagonists targeting estrogen receptor α-coactivator interaction in cancer therapy.

    abstract：:Estrogen receptor α (ERα) is a crucial target for ERα positive breast cancer treatment. Previous drug discovery efforts were focused on developing inhibitors that targeted the canonical ligand binding pockets of the ligand binding domain (LBD) of ERα. However, significant percentage of patients developed cancer relaps...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章,评审

    doi：10.1016/j.bmcl.2018.05.062

    authors： Qin W,Xie M,Qin X,Fang Q,Yin F,Li Z

    更新日期：2018-09-15 00:00:00

  • A bivalent ligand (KMN-21) antagonist for mu/kappa heterodimeric opioid receptors.

    abstract：:In an effort to develop antagonists for kappa-mu opioid receptor heterodimers, a series of bivalent ligands 3-6 containing kappa- and mu-antagonist pharmacophores were designed and synthesized. Evaluation of the series in HEK-293 cells revealed 4 (KMN-21) to selectively antagonize the activation of kappa-mu heterodime...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.10.045

    authors： Zhang S,Yekkirala A,Tang Y,Portoghese PS

    更新日期：2009-12-15 00:00:00

  • Hydroxyl substituted benzoic acid/cinnamic acid derivatives: Tyrosinase inhibitory kinetics, anti-melanogenic activity and molecular docking studies.

    abstract：:The inhibition of tyrosinase is an established strategy for treating hyperpigmentation. Our previous findings demonstrated that cinnamic acid and benzoic acid scaffolds can be effective tyrosinase inhibitors with low toxicity. The hydroxyl substituted benzoic and cinnamic acid moieties of these precursors were incorpo...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2019.126722

    authors： Nazir Y,Saeed A,Rafiq M,Afzal S,Ali A,Latif M,Zuegg J,Hussein WM,Fercher C,Barnard RT,Cooper MA,Blaskovich MAT,Ashraf Z,Ziora ZM

    更新日期：2020-01-01 00:00:00

  • An antitumor compound julibroside J28 from Albizia julibrissin.

    abstract：:A new triterpenoid saponin, julibroside J(28) (1), was isolated from the stem bark of Albizia julibrissin Durazz (Leguminosae) by using chromatographic method. The structure of 1 was established by spectroscopic methods. 1 displayed significant antitumor activity in vitro against PC-3M-1E8, Bel-7402, and HeLa cancer c...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2005.07.015

    authors： Liang H,Tong WY,Zhao YY,Cui JR,Tu GZ

    更新日期：2005-10-15 00:00:00

  • Discovery of novel S1P2 antagonists, part 3: Improving the oral bioavailability of a series of 1,3-bis(aryloxy)benzene derivatives.

    abstract：:The structure of the S1P2 antagonist 1 has been modified with the aim of improving its oral bioavailability. The chemical modification of the alkyl chain and carboxylic acid moieties of 1 led to significant improvements in the oral exposure of compounds belonging to this series. The optimization of the ring size of th...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2016.01.031

    authors： Kusumi K,Shinozaki K,Yamaura Y,Hashimoto A,Kurata H,Naganawa A,Otsuki K,Matsushita T,Sekiguchi T,Kakuuchi A,Yamamoto H,Seko T

    更新日期：2016-02-15 00:00:00

  • Ester and hydroxamate analogues of methionyl and isoleucyl adenylates as inhibitors of methionyl-tRNA and isoleucyl-tRNA synthetases.

    abstract：:The structure activity relationship on a series of ester and hydroxamate analogues of methionyl and isoleucyl adenylate has been investigated through introducing linkers between the 1'-position of ribose and adenine surrogates as methionyl-tRNA, and isoleucyl-tRNA synthetase inhibitors, respectively. The results indic...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(01)00095-6

    authors： Lee J,Kang SU,Kim SY,Kim SE,Kang MK,Jo YJ,Kim S

    更新日期：2001-04-23 00:00:00

  • Synthesis and anti-breast cancer activities of substituted quinolines.

    abstract：:Promising anti-breast cancer agents derived from substituted quinolines were discovered. The quinolines were readily synthesized in a large scale from a sequence of reactions starting from 4-acetamidoanisole. The Michael addition product was isolated as the reaction intermediate in the ring closing reaction of 4-amino...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2008.04.024

    authors： Shi A,Nguyen TA,Battina SK,Rana S,Takemoto DJ,Chiang PK,Hua DH

    更新日期：2008-06-01 00:00:00

  • Identification of a novel series of selective 5-HT7 receptor antagonists.

    abstract：:Novel 5-HT(7) receptor antagonists containing the benzocycloheptanone core were identified from high throughput screening. Molecular modelling and SAR studies have converted these intractable hits into a more potent, selective and tractable series, exemplified by compound (25), SB-691673. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(03)00077-5

    authors： Forbes IT,Cooper DG,Dodds EK,Douglas SE,Gribble AD,Ife RJ,Lightfoot AP,Meeson M,Campbell LP,Coleman T,Riley GJ,Thomas DR

    更新日期：2003-03-24 00:00:00

  • Synthesis and antihormonal properties of novel 11β-benzoxazole-substituted steroids.

    abstract：:Early studies led to the identification of 11β-aryl-4',5'-dihydrospiro[estra-4,9-diene-17β,4'-oxazole] analogs with potent and more selective antiprogestational activity compared to antiglucocorticoid activity than mifepristone. In the present study, we replaced the 4'-dimethylaminophenyl group of mifepristone with th...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2011.12.110

    authors： Jin C,Fix SE,Kepler JA,Cook CE

    更新日期：2012-02-15 00:00:00

  • Novel targeting strategy based on multimeric ligands for drug delivery and molecular imaging: homooligomers of alpha-MSH.

    abstract：:Homooligomers constructed with 4- and 6-amino acid fragments of melanocortin (alpha-MSH) bind with higher affinity and with apparent cooperativity to melanocortin receptor, compared to their constituent monomers. Individual ligands were tethered with various spacers of different length and rigidity and the influence o...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2003.09.079

    authors： Vagner J,Handl HL,Gillies RJ,Hruby VJ

    更新日期：2004-01-05 00:00:00