Abstract:
:Developing methods to incorporate protein flexibility into structure-based drug design is an important challenge. Our approach uses multiple protein structures (MPS) to create a receptor-based pharmacophore model of the desired target. We have previously demonstrated the success of the method by applying it to human immunodeficiency virus-1 protease (HIV-1p). Our models, based on an apo structure, discriminated known HIV-1p inhibitors from druglike inactive compounds and also accurately identified bound conformations of known inhibitors. Here, we test the method by applying it to all three unbound crystal structures of HIV-1p. We have also improved our method with denser probe mapping of the binding site and refined our selection criteria for pharmacophore elements. Our improved protocol has led to the development of a consistent 8-site pharmacophore model for HIV-1p, which is independent of starting structure, and a robust MPS pharmacophore method that is more amenable to automation.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Meagher KL,Lerner MG,Carlson HAdoi
10.1021/jm050755msubject
Has Abstractpub_date
2006-06-15 00:00:00pages
3478-84issue
12eissn
0022-2623issn
1520-4804journal_volume
49pub_type
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journal_title:Journal of medicinal chemistry
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更新日期:2016-09-08 00:00:00
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journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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abstract::A novel series of C(3)-substituted piperdinylindoles were developed as nociceptin opioid receptor (NOP) partial agonists to explore a pharmacological hypothesis that NOP partial agonists would afford a dual pharmacological action of attenuating Parkinson's disease (PD) motor symptoms and development of levodopa-induce...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b02134
更新日期:2020-03-12 00:00:00
abstract::To enhance the ability of indirubin derivatives to inhibit CDK2/cyclin E, a target of anticancer agents, we designed and synthesized a new series of indirubin-3'-oxime derivatives with combined substitutions at the 5 and 5' positions. A molecular docking study predicted the binding of derivatives with OH or halogen su...
journal_title:Journal of medicinal chemistry
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更新日期:2010-05-13 00:00:00
abstract::PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is crucial for maturation of ribosomes and has been implicated in several diseases. We recently disclosed a highly potent, selective, and cell-active allosteric inhibitor of PRMT3, compound 4. Here, we report comprehensive struct...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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更新日期:2018-02-08 00:00:00
abstract::(3-Phenyl-7-flavonoxy)propanolamines have been shown to exhibit antihypertensive activity in spontaneously hypertensive rats. Although they are structurally similar to classical beta-adrenergic blocking compounds, their activity is not due to inhibition of beta-adrenoceptors. In the present study, a series of simple f...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00121a034
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journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm800180e
更新日期:2008-06-12 00:00:00
abstract::Selected derivatives of 9-oxo-1H,9H-benzothiopyrano[2,3-d]-1,2,3-triazole, a new heterocyclic ring system, and their S-oxides have been prepared and evaluated for antiallergic activity in the rat passive cutaneous anaphylaxis screen. Several of the compounds show intravenous potencies similar to or greater than that o...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00368a021
更新日期:1984-02-01 00:00:00
abstract::Several novel azulene-containing retinoids were prepared and evaluated for their ability to suppress carcinogen-induced neoplastic transformation and to concomitantly up-regulate gap junctional communication in the in vitro mouse fibroblast C3H/10T1/2 cell bioassay. The azulenic retinoids were divided into two groups:...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00073a013
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abstract::Procedures were developed for the synthesis of exo-(2'-chloro-5-pyridinyl)-7-(endo and exo)-amino[2.2.1]heptanes (3a and 3b). The compounds were evaluated for binding to the alpha4beta2 and alpha7 nicotinic acetylcholine receptors (nAChRs), for pharmacological activity in the mouse tail-flick and hot-plate assays, and...
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更新日期:2005-11-17 00:00:00
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pub_type: 杂志文章
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更新日期:2016-02-11 00:00:00
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journal_title:Journal of medicinal chemistry
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doi:10.1021/jm960506l
更新日期:1997-04-11 00:00:00
abstract::The discovery of selective endothelin (ET) receptor antagonists will facilitate identification of the physiological and pathological roles for ET and its isopeptides. Structure-activity studies of the C-terminal hexapeptide of ET have been carried out to elucidate those amino acids important for receptor binding and a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00070a001
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abstract::With a view to identify novel and biocompatible neuroprotectants, we designed nucleoside 5'-thiophosphate analogues, 6-11. We identified 2-SMe-ADP(α-S), 7A, as a most promising neuroprotectant. 7A reduced ROS production in PC12 cells under oxidizing conditions, IC50 of 0.08 vs 21 μM for ADP. Furthermore, 7A rescued pr...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b00575
更新日期:2015-11-12 00:00:00
abstract::A series of conformationally locked N-glycosides having a cis-1,2-fused pyranose-1,3-oxazoline-2-thione structure and bearing different substituents at the exocyclic sulfur has been prepared. The polyhydroxylated bicyclic system was built in only three steps by treatment of the corresponding readily available 1,2-anhy...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm3006178
更新日期:2012-08-09 00:00:00
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journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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journal_title:Journal of medicinal chemistry
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更新日期:2006-09-07 00:00:00
abstract::Modulation of sphingosine 1-phosphate (S1P) signaling represents a solid opportunity for multiple sclerosis (MS) treatment. In this issue, a team at Novartis reports on the identification of the first direct S1P lyase (S1PL) inhibitors as new MS agents. One of the most potent inhibitors reported in their work was demo...
journal_title:Journal of medicinal chemistry
pub_type: 评论,杂志文章
doi:10.1021/jm500845y
更新日期:2014-06-26 00:00:00
abstract::A series of quinolone and naphthyridine antibacterial agents possessing as the C7-heterocycle bicyclic 2,5-diazabicyclo[n.2.m]alkanes, where n = 2, 3 and m = 1, 2, and a series including 4-aminopiperidine and 3-amino-8-azabicyclo[3.2.1]octanes have been prepared and evaluated in vitro and in vivo for antibacterial act...
journal_title:Journal of medicinal chemistry
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doi:10.1021/jm00106a029
更新日期:1991-02-01 00:00:00