Abstract：
:Molecular docking studies of carbohydrate derivatives in protein binding sites are often challenging because of water-mediated interactions and the inherent flexibility of the many terminal hydroxyl groups. Using the recognition process between heat-labile enterotoxin from Escherichia coli and ganglioside GM1 as a paradigm, we developed a modeling protocol that includes incremental conformational flexibility of the ligand and predicted water interactions. The strategy employs a modified version of the Monte Carlo docking program AUTODOCK and water affinity potentials calculated with GRID. After calibration of the protocol on the basis of the known binding modes of galactose and lactose to the toxin, blind predictions were made for the binding modes of four galactose derivatives: lactulose, melibionic acid, thiodigalactoside, and m-nitrophenyl-alpha-galactoside. Subsequent crystal structure determinations have demonstrated that our docking strategy can predict the correct binding modes of carbohydrate derivatives within 1.0 A from experiment. In addition, it is shown that repeating the docking simulations in each of the seemingly identical binding sites of the multivalent toxin increases the chance of finding the correct binding mode.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Minke WE,Diller DJ,Hol WG,Verlinde CLdoi
10.1021/jm980472ckeywords:
subject
Has Abstractpub_date
1999-05-20 00:00:00pages
1778-88issue
10eissn
0022-2623issn
1520-4804pii
jm980472cjournal_volume
42pub_type
杂志文章abstract：:The synthesis, pharmacological evaluation, and structure-activity relationships (SARs) of a series of novel pyrroloquinoxalines and heteroaromatic-related derivatives are described. The new pyrroloquinoxaline-related ligands were tested in rat cortex, a tissue expressing high density of 5-HT(3) receptors, and on NG108...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990151g
更新日期：1999-10-21 00:00:00
abstract：:Anthelmintic efficacies of a series of 6-substituted methyl imidazo[1,2-alpha]pyridine-2-carbamates were compared to similarly substituted benzimidazole-2-carbamates. With only one exception, methyl 6-benzoylimidazo[1,2-alpha]pyridine-2-carbamate, both classes of compounds exhibited similar activity vs. Nematospiroide...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00144a030
更新日期：1981-12-01 00:00:00
abstract：:Mycophenolic alcohol (MPAlc), obtained by reduction of the carboxylic group of mycophenolic acid (MPA), was coupled with 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (4) in the presence of diisopropylcarbodiimide (DIC) to give P1-(2',3'-O-isopropylideneadenosin-5'-yl)-P2-(mycophenolic alcohol-6'-yl)met...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970705k
更新日期：1998-02-12 00:00:00
abstract：:Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00260
更新日期：2019-07-25 00:00:00
abstract：:Adenosine receptor-binding profiles in rat brain tissues and antihypertensive effects in spontaneously hypertensive rats (SHR) of a series of 2-(cycloalkylalkynyl)adenosines (2-CAAs) and their congeners are described. The structure-activity relationship of this series of compounds is discussed, focusing on the length ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00090a017
更新日期：1992-06-12 00:00:00
abstract：:Dual-acting kappa opioid receptor (KOR) agonist and mu opioid receptor (MOR) partial agonist ligands have been put forward as potential treatment agents for cocaine and other psychostimulant abuse. Members of the orvinol series of ligands are known for their high binding affinity to both KOR and MOR, but efficacy at t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm301543e
更新日期：2013-04-25 00:00:00
abstract：:In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401329s
更新日期：2014-03-13 00:00:00
abstract：:Five renin inhibitors were cocrystallized with endothiapepsin, a fungal enzyme homologous to renin. Crystal structures of inhibitor-bound complexes have provided invaluable insight regarding the three-dimensional structure of the aspartic proteinase family of enzymes, as well as the steric and polar interactions that ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00076a008
更新日期：1993-11-26 00:00:00
abstract：:Inhibition of the cell cycle kinase, cyclin-dependent kinase-4 (Cdk4), is expected to provide an effective method for the treatment of proliferative diseases such as cancer. The pyrido[2,3-d]pyrimidin-7-one template has been identified previously as a privileged structure for the inhibition of ATP-dependent kinases, a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049355+
更新日期：2005-04-07 00:00:00
abstract：:A series of new 9-phenanthrene amino alcohols has been prepared in which each compound bears from one to five halogen or halogen-containing moieties. A number of these compounds are extremely active against Plasmodium berghei in the mouse. Some structural requirements for optimal efficacy are considered. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00244a012
更新日期：1975-10-01 00:00:00
abstract：:We present a comprehensive study of the performance of fast scoring functions for library docking using the program FlexX as the docking engine. Four scoring functions, among them two recently developed knowledge-based potentials, are evaluated on seven target proteins whose binding sites represent a wide range of siz...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0003992
更新日期：2001-03-29 00:00:00
abstract：:2,6,8-Trichloro-7-methylpurine (3) was converted to 2-chloro-8,9-dihydro-7-methyl-8-thioxopurin-6(1H)-one (5) by utilizing the difference in reactivity of the 2-, 6-, and 8-positions in the trichloropurine ring system to nucleophilic displacement. Compound 5 was subsequently glycosylated with 1-O-acetyl-2,3,5-tri-O-be...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00170a013
更新日期：1990-08-01 00:00:00
abstract：:Renin inhibitors 2-4 with the D-Lys renin inhibitory peptide (RIP) sequence, but containing Leu psi[CH2O]Ala (2), Leu psi[CH2O]Val (3), and Leu psi[CH2O]Leu (4) at the P1-P1' site, were of a comparable potency to RIP. N-Terminal Boc-protected inhibitors containing Pro psi[CH2O]Phe in positions P4-P3 were potent inhibi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00398a029
更新日期：1988-03-01 00:00:00
abstract：:In drug discovery, it is essential to identify binding sites on protein surfaces that drug-like molecules could exploit to exert a biological effect. Both X-ray crystallography and NMR experiments have demonstrated that organic solvents bind precisely at these locations. We show that this effect is reproduced using mo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801385d
更新日期：2009-04-23 00:00:00
abstract：:Mercaptopurine (6-MP), thioguanine (6-TG), and azathioprine (AZA) are purine antimetabolites introduced as anticancer or immunosuppressive drugs decades ago. Methylated AZA, called MAZA, is among the investigational drugs. The present study compares MAZA to the widely recognized drugs AZA, 6-MP, and 6-TG with respect ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0495273
更新日期：2005-06-30 00:00:00
abstract：:The pathology of chronic dermal ulcers is characterized by excessive proteolytic activity which degrades extracellular matrix (required for cell migration) and growth factors and their receptors. The overexpression of MMP-3 (stromelysin-1) and MMP-13 (collagenase-3) is associated with nonhealing wounds, whereas active...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0308038
更新日期：2003-07-31 00:00:00
abstract：:The pyridine C-nucleosides 5-beta-D-ribofuranosylnicotinamide and its N-methylpyridinium derivative (1 and 2), which are isosteric and isoelectronic, respectively, to nicotinamide nucleoside were synthesized. Condensation of 3-bromo-5-lithiopyridine with 2,4:3,5-di-O-benzylidene-D-aldehydoribose (7) afforded an allo/a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00388a030
更新日期：1987-05-01 00:00:00
abstract：:We previously reported that substrates of semicarbazide-sensitive amine oxidase in combination with low concentrations of vanadate exert potent insulin-like effects. Here we performed homology modeling of the catalytic domain of mouse SSAO/VAP-1 and searched through chemical databases to identify novel SSAO substrates...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0499211
更新日期：2004-09-23 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：:Twenty-two structural derivatives of clonidine [2-(2,6-dichlorophenylimino)imidazolidine] have been synthesized and their main physicochemical parameters (log P, deltaRM, pKa) determined. Quantitative correlations between the peripheral alpha-mimetic action (pithed rats) and physicochemical parameters pointed out the ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00230a014
更新日期：1976-08-01 00:00:00
abstract：:The efficacious dose of a drug is perhaps the most holistic metric reflecting its therapeutic potential. Dose is predicted at many stages in drug discovery and development. Prior to the 1990s, dose prediction was limited to the drug "working" at a reasonable dose and dose regimen in an animal model. Through the early ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01365
更新日期：2020-06-25 00:00:00
abstract：:Extension of the structure-activity relationship studies that led to the discovery of the nonsedating potent muscle relaxant, antiinflammatory, and analgesic agent (E)-2-(4,6-difluoro-1-indanylidene)acetamide, 1, has given rise to (E)-2-(4-chloro-6-fluoro-1-indanylidene)-N-methylacetamide, 2. Compound 2 is a potent an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020068k
更新日期：2003-01-30 00:00:00
abstract：:There is reported the first four members of heteroarotinoids, the names of which are ethyl (E)-p-[2-(4,4-dimethylthiochroman-6-yl)propenyl]benzoate (1b), ethyl (E)-p-[2-(4,4-dimethylchroman-6-yl)propenyl]benzoate (1c), ethyl (E)-p-[2-(4,4-dimethyl-1-oxothiochroman-6-yl)propenyl]benzoate (1d), and (E)-p-[2-(4,4-dimethy...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00379a021
更新日期：1985-01-01 00:00:00
abstract：:New 5'-O-carbonate prodrugs of zidovudine (AZT) have been synthesized in order to enhance its uptake by HIV-1 infected cells, to improve its anti-HIV potency, and to optimize the intramolecular cyclic rearrangement process related to the 5'-O-(4-hydroxybutyl) carbonate moiety. Evidence of this prodrug rearrangement wa...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010863i
更新日期：2001-08-30 00:00:00
abstract：:Partially hydrogenated derivatives of the new heterocyclic ring systems benz[d]indolo[2,3-g]azecine and bisindolo[3,2-d][2, 3-g]azecine were synthesized starting from lactones and amines via the described synthetic methods. In binding assays with rat striatal receptors, 7-methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indol...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9911478
更新日期：2000-05-18 00:00:00
abstract：:A conformationally defined retinoic acid analog (1) which contains a dimethylene bridge to maintain the 6-s-trans orientation for two terminal double bonds in the polyene chain was synthesized. A Reformatsky reaction was utilized to extend the polyene chain of the starting enone, which provided exclusively the 9Z-conf...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00052a009
更新日期：1994-12-23 00:00:00
abstract：:1-Aroylindoline, 1-aroyl-1,2,3,4-tetrahydroquinoline, and 1-aroylindole derivatives were synthesized and evaluated for anticancer activity. The 4-amino and 4-hydroxy-1-aroylindoles 26 and 27 with IC 50 of 0.9 and 0.6 microM, respectively, exhibited antitubulin activity superior or comparable to that of colchicine and ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800150d
更新日期：2008-07-24 00:00:00
abstract：:In humans, bitter taste is mediated by 25 TAS2Rs. Many compounds, including certain active pharmaceutical ingredients, excipients, and nutraceuticals, impart their bitter taste (or in part) through TAS2R8 activation. However, effective TAS2R8 blockers that can either suppress or reduce the bitterness of these compound...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00388
更新日期：2020-05-14 00:00:00
abstract：:Several norindenoisoquinolines substituted with methoxy or methylenedioxy groups have been prepared and their anticancer properties evaluated in cancer cell cultures and in topoisomerase I inhibition assays. 2,3-Dimethoxy-8,9-methylenedioxy-11H-indeno[1,2-c]isoquinoline hydrochloride (14) is a strong topoisomerase I i...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050076b
更新日期：2005-07-28 00:00:00
abstract：:While adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features that contribute more to off-target activity can also be very effective. Reported here is our successful effort of improv...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00033
更新日期：2017-03-09 00:00:00
