Abstract:
:DoMCoSAR is a novel approach for statistically determining the docking mode that is consistent with a structure-activity relationship. The approach establishes the binding mode for the compounds in a chemical series with the assumption that all molecules exhibit the same binding mode. It involves three stages. In the first stage all molecules that belong to a given chemical series are docked to the active site of the protein target. The only bias used in the docking at this stage involves the location of the protein binding site. Coordinates of the common substructure (CS) that results from the unbiased docking are then clustered to establish the major substructure docking modes. In the second stage all molecules are docked to the major docking modes (MDMs) with constraints based on the common substructure. The third stage generates, for the major docking modes, interaction-based descriptors that include electrostatic, VDW, strain, and solvation contributions. The problem of docking mode evaluation is now reduced to the question of which descriptor set is more predictive. To establish a quantitative comparison of the descriptor sets associated with the major docking modes, we use 50 instances of random 4-fold cross-validation. For each 4-fold cross-validation the predictive squared correlation coefficient (R(2)) is computed. t-Tests are applied to establish significance of the differences in mean R(2) for one docking mode versus another. We test the methodology on two test cases: HIV-1 protease inhibitors (Holloway et al. J. Med. Chem. 1995, 38, 305-317) and vascular endothelial growth factor (VEGF) receptor tyrosine kinase oxoindoles (Sun et al. J. Med. Chem. 1998, 41, 2588-2603). For both test cases there is statistically significant preference for the binding mode consistent with the X-ray structure. The appeal of this methodology is that researchers gain the objectivity of statistical justification for the selected docking mode. The methodology is relatively insensitive to subtle variations of the protein structure that include, but are not limited to, side chain and small backbone rearrangement during binding. In addition, predictive models that result from the approach can be used to further optimize chemical series.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Vieth M,Cummins DJdoi
10.1021/jm990609ekeywords:
subject
Has Abstractpub_date
2000-08-10 00:00:00pages
3020-32issue
16eissn
0022-2623issn
1520-4804pii
jm990609ejournal_volume
43pub_type
杂志文章abstract::Structure-activity relationships within a series of highly potent 2-carboxyindole-based factor Xa inhibitors incorporating a neutral P1 ligand are described with particular emphasis on the structural requirements for addressing subpockets of the factor Xa enzyme. Interactions with the subpockets were probed by systema...
journal_title:Journal of medicinal chemistry
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更新日期:2005-07-14 00:00:00
abstract::The recently discovered nicotinic agonist pyrido[3,4-b]norhomotropane [corrected] (PHT) as well as its N-methyl and 2'-methyl derivatives (syntheses reported herein) were compared with nicotine, nornicotine, and anatoxin a in a series of in vitro and in vivo assays. The results reveal that PHT possesses activity compa...
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abstract::A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expr...
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更新日期:2014-08-14 00:00:00
abstract::The photolabile (diazomethyl)carbonyl function was introduced into the 8-position of 2-(N,N-di-n-propyl-amino)-1,2,3,4-tetrahydronaphthalene in three ways, resulting in the ether 8-[[(diazomethyl)carbonyl]methoxy]-2-(N,N-di-n-propylamino)-1,2,3,4- tetrahydronaphthalene (2), the ester 8-(diazoacetoxy)-2-(N,N-di-n-propy...
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abstract::Deregulation of CK1 (casein kinase 1) activity can be involved in the development of several pathological disorders and diseases such as cancer. Therefore, research interest in identifying potent CK1-specific inhibitors is still increasing. A previously published potent and selective benzimidazole-derived CK1δ/ε-speci...
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更新日期:2014-10-09 00:00:00
abstract::Targeted polypharmacology of kinases has emerged as a promising strategy to design efficient and safe therapeutics. Here, we perform a systematic study of kinase-ligand binding modes for the human structural kinome at scale (208 kinases, 1777 unique ligands, and their complexes) by integrating chemical genomics and st...
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更新日期:1977-01-01 00:00:00
abstract::To search for new antiestrogens more effective in treating breast cancers, we explored alternatives to the acrylic acid side chain used in many antiestrogens. To facilitate our search, we used a simple adamantyl ligand core that by avoiding stereochemical issues enabled rapid synthesis of acrylate ketone, ester, and a...
journal_title:Journal of medicinal chemistry
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更新日期:2017-07-27 00:00:00
abstract::Substituted 6-anilinouracils were found to be potent inhibitors of the replication-specific enzyme, DNA polymerase III, from Bacillus subtilis. Inhibition potency was maximized by inclusion of small alkyl groups or halogens in the meta and para positions of the phenyl ring; polar substituents decreased activity consi...
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doi:10.1021/jm00175a007
更新日期:1980-01-01 00:00:00
abstract::For disease network intervention, up-regulating enzyme activities is equally as important as down-regulating activities. However, the design of enzyme activators presents a challenging route for drug discovery. Previous studies have suggested that activating 15-lipoxygenase (15-LOX) is a promising strategy to interven...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b01011
更新日期:2016-05-12 00:00:00
abstract::A variety of derivatives of 2-pyridinecarboxaldehyde 1-oxide benzenesulfonylhydrazone, containing substituents on the benzene or pyridine rings as well as on the nitrogen atom which is bonded directly to the sulfonyl group, have been synthesized. The antineoplastic activity of these compounds has been assessed in mice...
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doi:10.1021/jm00180a010
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abstract::G-protein-coupled receptor 52 (GPR52) is an orphan Gs-coupled G-protein-coupled receptor. GPR52 inhibits dopamine D2 receptor signaling and activates dopamine D1/N-methyl-d-aspartate receptors via intracellular cAMP accumulation, and therefore, GPR52 agonists may have potential as a novel class of antipsychotics. A se...
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更新日期:2014-06-26 00:00:00
abstract::4-Amino-5-arylpyrimidines were synthesized by a variety of methods and have demonstrated antiinflammatory activity in the carrageenan-induced edema in the rat but displayed little activity against adjuvant-induced arthritis in rats or against uv-induced erythema in guinea pigs. ...
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pub_type: 杂志文章
doi:10.1021/jm00240a021
更新日期:1975-06-01 00:00:00
abstract::The endogenous peptides somatostatin (SRIF) and substance P comprise very different structures. Although both bind G-protein-coupled receptors, the SRIF receptors (SSTR 1-5) recognize SRIF and related peptides which retain its beta-turn such as the potent cyclic hexapeptide SRIF agonist L-363,301 (6a), but not substan...
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更新日期:1996-06-21 00:00:00
abstract::Six new analogues of 1α,25-dihydroxy-19-norvitamin D(3) (3a-4b, 5, and 6) were prepared by a convergent synthesis applying the Wittig-Horner reaction as a key step. The influence of methyl groups at C-22 on their biological activity was examined. It was established that both in vitro and in vivo activity is strongly d...
journal_title:Journal of medicinal chemistry
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doi:10.1021/jm300187x
更新日期:2012-05-10 00:00:00
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更新日期:2018-10-11 00:00:00
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abstract::Nicotinic acetylcholine receptors (nAChRs) have been investigated for developing drugs that can potentially treat various central nervous system disorders. Considerable evidence supports the hypothesis that modulation of the cholinergic system through activation and/or desensitization/inactivation of nAChR holds promi...
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更新日期:2014-10-23 00:00:00
abstract::Intravenous administration of N-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin (4) induces an acute toxic reaction, killing animals in a few minutes. This results from its positive charge at physiological pH combined with its propensity to form large aggregates in aqueous solutions. Negatively charged N-capped ve...
journal_title:Journal of medicinal chemistry
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abstract::Multiple recent studies have focused on unraveling the content of the medicinal chemist's toolbox. Here, we present an investigation of chemical reactions and molecules retrieved from U.S. patents over the past 40 years (1976-2015). We used a sophisticated text-mining pipeline to extract 1.15 million unique whole reac...
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更新日期:2016-05-12 00:00:00
abstract::Early studies in these laboratories of peptidomimetic structures containing a basic P1 moiety led to the highly potent and selective thrombin inhibitors 2 (Ki = 5.0 nM) and 3 (Ki = 0.1 nM). However, neither attains significant blood levels upon oral administration to rats and dogs. With the aim of improving pharmacoki...
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abstract::Synthesis and opioid radioreceptor assay data on analogues closely related to 6-desoxy-6-spiro-alpha-methylene-gamma-lactone 5a, a compound with irreversible activity in this assay, are reported. Saturated lactones (7a,b), endocyclic alpha, beta-unsaturated gamma-lactones (8a,b and 9a), and 6 alpha,7 alpha-fused alpha...
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abstract::A number of cycloalkyl substituents (from C-3 to C-8) have been introduced on the 6-amino group of adenosine, 1-deazaadenosine, and 2'-deoxyadenosine, bearing or not a chlorine atom at the 2-position, to evaluate the influence on the A(1) and A(2A) affinity of steric hindrance and lipophilicity. Furthermore, the guano...
journal_title:Journal of medicinal chemistry
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abstract::HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimizatio...
journal_title:Journal of medicinal chemistry
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更新日期:2014-03-13 00:00:00
abstract::Noncovalent proteasome inhibitors introduce an alternative mechanism of inhibition to that of covalent inhibitors used in cancer therapy. Starting from a noncovalent linear mimic of TMC-95A, a series of dimerized inhibitors using polyaminohexanoic acid spacers has been designed and optimized to target simultaneously t...
journal_title:Journal of medicinal chemistry
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更新日期:2013-04-25 00:00:00