Abstract：
:A new computational method for the in situ generation of small molecules within the binding site of a protein is described. The method has been evaluated using two well-studied systems, dihydrofolate reductase and thymidylate synthase. The method has also been used to guide improvements to inhibitors of HIV-1 protease. One such improvement resulted in a compound selected for preclinical studies as an antiviral agent against AIDS.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Gehlhaar DK,Moerder KE,Zichi D,Sherman CJ,Ogden RC,Freer STdoi
10.1021/jm00003a010subject
Has Abstractpub_date
1995-02-03 00:00:00pages
466-72issue
3eissn
0022-2623issn
1520-4804journal_volume
38pub_type
杂志文章abstract：:Vacuolar type ATPase (V-ATPase) has recently emerged as a promising novel anticancer target based on extensive in vitro and in vivo studies with archazolids, complex polyketide macrolides, which present the most potent V-ATPase inhibitors known to date. Herein, we report a biomimetic, one-step preparation of archazoli...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01887
更新日期：2020-02-27 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
pub_type： 杂志文章
doi：10.1021/jm4002007
更新日期：2013-04-25 00:00:00
abstract：:A new approach to rapidly score protein-ligand interactions is tested on several protein-ligand systems. Results using this approach - the OWFEG free energy grid - are quite promising and are generally in better agreement with experiment (in some cases much better) than those obtained employing scoring techniques curr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000375v
更新日期：2001-02-15 00:00:00
abstract：:N-Aminated nucleoside complexes of cis-dichloroplatinum(II) were synthesized, and their antitumor activities against L1210 cells in mice and in vitro were studied. While the native nucleosides failed to show any antitumor activity, the complexes exhibited high antitumor activity and had no nephrotoxicity in mice. Stud...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00370a006
更新日期：1984-04-01 00:00:00
abstract：:In only four chemical steps from naturally occurring artemisinin (1), trioxane dimers 6 and 7 were prepared on a multigram scale in overall 32-44% yields. In mice, both isonicotinate N-oxide dimer 6 and isobutyric acid dimer 7 were considerably more antimalarially efficacious than clinically used sodium artesunate (2)...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0303711
更新日期：2004-02-26 00:00:00
abstract：:Proteins which bind methylated lysines ("readers" of the histone code) are important components in the epigenetic regulation of gene expression and can also modulate other proteins that contain methyl-lysine such as p53 and Rb. Recognition of methyl-lysine marks by MBT domains leads to compaction of chromatin and a re...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200045v
更新日期：2011-04-14 00:00:00
abstract：:A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactiva...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100957a
更新日期：2010-12-09 00:00:00
abstract：:Inhibitor of secreted frizzled related protein-1 (sFRP-1) would be a novel potential osteogenic agent, since loss of sFRP-1 affects osteoblast proliferation, differentiation, and activity, resulting in improved bone mineral density, quality, and strength. We have identified small molecule diarylsulfone sulfonamide der...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801069w
更新日期：2008-12-25 00:00:00
abstract：:The dopamine D(3) receptor is recognized as a potential therapeutic target for the treatment of various neurological and psychiatric disorders. Targetting high affinity and D(3) versus D(2) receptor-preferring ligands, the partial agonist BP 897 was taken as a lead structure. Variations in the spacer and the aryl moie...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030836n
更新日期：2003-08-28 00:00:00
abstract：:The interaction between β-catenin and B-cell CLL/lymphoma 9 (BCL9), critical for the transcriptional activity of β-catenin, is mediated by a helical segment from BCL9 and a large binding groove in β-catenin. Design of potent, metabolically stable BCL9 peptides represents an attractive approach to inhibit the activity ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm201125d
更新日期：2012-02-09 00:00:00
abstract：:Glycogen synthase kinase -3 (GSK-3) is a key enzyme involved in numerous physiological events and in major diseases, such as Alzheimer's disease, diabetes, and cardiac hypertrophy. Indirubins are bis-indoles that can be generated from various natural sources or chemically synthesized. While rather potent and selective...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800648y
更新日期：2008-10-23 00:00:00
abstract：:A series of substituted phenyl analogues of 5-[[4-(4,5-dihydro-2-oxazolyl) phenoxy]alkyl]-3-methylisoxazoles has been synthesized and evaluated in vitro against several human rhinovirus (HRV) serotypes. Substituents in the 2-position greatly enhanced activity when compared to the unsubstituted compound. Many of these ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00385a021
更新日期：1987-02-01 00:00:00
abstract：:A six-stage stereoselective synthesis of indanyl-7-(3'-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3'-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pK(i) > 9.0) with good aqueous solubility. E...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm201287w
更新日期：2012-01-26 00:00:00
abstract：:A novel series of 3,4-dihydroxychalcones was synthesized to evaluate their effects against 5-lipoxygenase and cyclooxygenase. Almost all compounds exhibited potent inhibitory effects on 5-lipoxygenase with antioxidative effects, and some also inhibited cyclooxygenase. The 2',5'-disubstituted 3,4-dihydroxychalcones wit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00076a019
更新日期：1993-11-26 00:00:00
abstract：:1-Methyl-5-(3-azido-2,3-dideoxy-beta-D-erythro-pentofuranosyl)uracil (C-AZT), a C-nucleoside isostere of the potent anti-AIDS nucleoside 3'-azido-3'-deoxythymidine (AZT), was synthesized. 1-Methyl-2'-deoxy-5'-O-tritylpseudouridine (2a) was oxidized with CrO3/pyridine/Ac2O complex to 1-methyl-5-(5-O-trityl-beta-D-glyce...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00169a030
更新日期：1990-07-01 00:00:00
abstract：:Water soluble 2'-taxol poly(ethylene glycol) (PEG) esters have been synthesized and shown to function in vitro as prodrugs. However, in vivo experiments clearly establish that in order for these prodrugs to behave in a predictable fashion, the molecular weight of PEG must be of such magnitude so as to maintain a t1/2(...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950475e
更新日期：1996-01-19 00:00:00
abstract：:A series of 2,3-dihydrobenzofuran-5-acetic acids and related compounds was prepared as potential antiinflammatory agents. As measured by the carrageenan-induced edema method for the preliminary screening test, introduction of a methyl group alpha to the acetic acid function enhanced the antiinflammatory activity, and ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00224a020
更新日期：1976-02-01 00:00:00
abstract：:A number of fluorenyl and diphenylmethane analogues of verapamil, chosen as having the same substituents arranged in different ways around the quaternary carbon, were synthesized in order to evaluate the importance of the stereoisomerism at that point of the molecule. The compounds were tested with the Langendorff tec...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00149a014
更新日期：1985-11-01 00:00:00
abstract：:Replacing the 1alpha-OH group of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (calcitriol) by a 1alpha-CHF(2) group and incorporating a potentiating side chain produced two new hybrid analogs 6 and 7. Both of these two hybrid analogs are as transcriptionally active as calcitriol and are strongly antiproliferati...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0609925
更新日期：2006-12-14 00:00:00
abstract：:USP7 is a promising target for cancer therapy as its inhibition is expected to decrease function of oncogenes, increase tumor suppressor function, and enhance immune function. Using a structure-based drug design strategy, a new class of reversible USP7 inhibitors has been identified that is highly potent in biochemica...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00245
更新日期：2020-05-28 00:00:00
abstract：:Using a combination of iterative structure-based design and an analysis of oral pharmacokinetics and antiviral activity, AG1343 (Viracept, nelfinavir mesylate), a nonpeptidic inhibitor of HIV-1 protease, was identified. AG1343 is a potent enzyme inhibitor (Ki = 2 nM) and antiviral agent (HIV-1 ED50 = 14 nM). An X-ray ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9704098
更新日期：1997-11-21 00:00:00
abstract：:A series of conjugated hyaluronic acid particles (HAP), composed of a hydrophobic anticancer drug core and hydrophilic cyclodextrin/hyaluronic acid shell, were prepared through self-assembling and characterized by (1)H NMR titration, electron microscopy, zeta potential, and dynamic light-scattering experiments. The na...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm4014168
更新日期：2013-12-12 00:00:00
abstract：:Bivalent molecules containing two beta-turn mimics with side chains that correspond to hot-spots on the neurotrophin NT-3 were prepared. Binding assays showed the mimetics to be selective TrkC ligands, and biological assays showed one mimetic to be an antagonist of the TrkC receptor. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100148d
更新日期：2010-07-08 00:00:00
abstract：:A series of 4-amino[1,2,4]triazolo[4,3-a]quinoxalines has been prepared. Many compounds from this class reduce immobility in Porsolt's behavioral despair model in rats upon acute administration and may therefore have therapeutic potential as novel and rapid acting antidepressant agents. Optimal activity in this test i...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00170a031
更新日期：1990-08-01 00:00:00
abstract：:The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in v...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00743
更新日期：2018-09-13 00:00:00
abstract：:Tertiary EGFRC797S mutation induced resistance against osimertinib (1) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFRL858R/T790M/C797S inhibitors. A representative compound, 8r-B,...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00576
更新日期：2019-08-08 00:00:00
abstract：:Previous work has shown that incorporation of either 1-aminocyclohexanecarboxylic acid (Ac6c) or alpha-methyl-p-phosphonophenylalanine ((alpha-Me)Ppp) in the phosphotyrosyl (pTyr) C-proximal position (pY + 1 residue) of Grb2 SH2 domain binding peptides confers high affinity. The tetralin-based (S)-2-amino-6-phosphonot...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0492709
更新日期：2005-02-10 00:00:00
abstract：:We present an RP-HPLC method, for the determination of logPoct values for neutral drugs, which combines ease of operation with high accuracy and which has been shown to work for a set of 36 molecules comprised largely of drugs. The general features of the method are as follows: (i) compound sparing (< or = 1 mL of a 3...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0000822
更新日期：2000-07-27 00:00:00
abstract：:Brain metastasis occurs in 20-40% of cancer patients. Treatment is mostly palliative, and the inability of most drugs to penetrate the brain presents one of the greatest challenges in the development of therapeutics for brain metastasis. Matrix metalloproteinase-2 (MMP-2) plays important roles in invasion and vascular...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401217d
更新日期：2013-10-24 00:00:00
abstract：:Recent trends in drug discovery include methods to identify dual and triple activating drugs. This approach is being successfully employed in malaria, cancer, asthma, insulin resistance, etc. Molecular field analysis has been employed in correlating pharmacological data and field parameters. In this paper we introduce...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049383s
更新日期：2005-04-21 00:00:00
