Abstract：
:It is now plausible to dock libraries of 10 million molecules against targets over several days or weeks. When the molecules screened are commercially available, they may be rapidly tested to find new leads. Although docking retains important liabilities (it cannot calculate affinities accurately nor even reliably rank order high-scoring molecules), it can often can distinguish likely from unlikely ligands, often with hit rates above 10%. Here we summarize the improvements in libraries, target quality, and methods that have supported these advances, and the open access resources that make docking accessible. Recent docking screens for new ligands are sketched, as are the binding, crystallographic, and in vivo assays that support them. Like any technique, controls are crucial, and key experimental ones are reviewed. With such controls, docking campaigns can find ligands with new chemotypes, often revealing the new biology that may be docking's greatest impact over the next few years.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Irwin JJ,Shoichet BKdoi
10.1021/acs.jmedchem.5b02008subject
Has Abstractpub_date
2016-05-12 00:00:00pages
4103-20issue
9eissn
0022-2623issn
1520-4804journal_volume
59pub_type
杂志文章,评审abstract：:Structural simplification of an antimitotic natural product podophyllotoxin with mimetic heterocyclic scaffolds constructed using multicomponent reactions led to the identification of compounds exhibiting low nanomolar antiproliferative and apoptosis-inducing properties. The most potent compounds were found in the dih...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200410r
更新日期：2011-06-23 00:00:00
abstract：:Five new P1-(steroid-21-yl)-P2-(1-beta-D-arabinofuranosylcytosin-5'-yl)pyro phosphates (ara-CDP-steroids), five 1-beta-D-arabinofuranosylcytosine 5'-O-(alkyl)phosphates (ara-CMP-alkyl esters), and two P1-(alkyl)-P2-(1-beta-D-arabinofuranosylcytosin-5'-yl)pyrophosphat e (ara-CDP-alkyl esters) have been prepared and eva...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00380a004
更新日期：1985-02-01 00:00:00
abstract：:All three amino-substituted 3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b]pyridazines (5, 19, and 20) structurally related to formycin A were prepared and tested for their antitumor and antiviral activity in cell culture. Dehydrative coupling of 4-amino-5-chloro-3-hydrazinopyridazine (7) with 3,4,6-tri-O-benzoyl-2,5-anh...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00127a024
更新日期：1989-07-01 00:00:00
abstract：:We report the synthesis and antiviral activity of a new family of non-nucleoside antivirals, derived from the 4-keto-1,2-oxathiole-2,2-dioxide (beta-keto-gamma-sultone) heterocyclic system. Several 4- and 5-substituted-5H-1,2-oxathiole-2,2-dioxide derivatives were found to have a selective inhibitory activity against ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm8014662
更新日期：2009-03-26 00:00:00
abstract：:As part of a study on the structure-activity relationship of antitumor-active tropolone derivatives, a series of bistropone analogues, related to potently active bistropolone 1a, were synthesized and tested for their antitumor activity in in vitro (KB cell) and in vivo (leukemia P388 in mice) systems. The methoxytropo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00390a022
更新日期：1987-07-01 00:00:00
abstract：:Isosorbide-2-benzyl carbamate-5-benzoate is a highly potent and selective BuChE inhibitor. Meanwhile, isosorbide-2-aspirinate-5-salicylate is a highly effective aspirin prodrug that relies on the salicylate portion to interact productively with human BuChE. By integrating the salicylate group into the carbamate design...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9014845
更新日期：2010-02-11 00:00:00
abstract：:The synthesis of several 8-carboxy-6-sulfamyldibenz[b,f][1,4]oxazepines and -thiazepines is described. The results of diuretic screening lend support to the thesis that activity is strongly dependent on the conformational mobility of 4-substituents in the 3-amino-5-sulfamylbenzoic acids. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00206a027
更新日期：1978-08-01 00:00:00
abstract：:The protein kinase PfCLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for the survival of blood stage Plasmodium falciparum. We recently validated PfCLK3 as a drug target in malaria that offers prophylactic, transmission blocking, and curative potential. Herein, we descri...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00451
更新日期：2020-09-10 00:00:00
abstract：:Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade. To investigate the potential of FXIa inhibitors as safe anticoagulants, a series of potent, selectiv...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060978s
更新日期：2006-12-28 00:00:00
abstract：:Two prototype N-methyl-4-thio-substituted cyclophosphamide (CP) derivatives (5 and 6), prodrugs of 4-hydroxycyclophosphamide (4-HO-CP), were designed to undergo oxidative N-demethylation to release the active alkylating agent. These prodrugs were chemically stable until oxidatively N-demethylated in the presence of he...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00005a012
更新日期：1995-03-03 00:00:00
abstract：:Various basic esters of nitrogen (2) and carbocyclic (3 and 4) analogs of cannabinoids were synthesized using dicyclohexylcarbodiimide in methylene chloride. The compounds in the three series werw studied in selected pharmacological tests in mice, rats, dogs, and cats. It was shown that making the basic ester from the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00226a002
更新日期：1976-04-01 00:00:00
abstract：:A series of both aliphatic and aromatic amides and aromatic amidines derived from 2-amino-1,10-phenanthroline (3) according to the Topliss scheme were synthesized and subsequently tested for antimycoplasmal potency. Although the compounds themselves showed no activity, in the presence of a nontoxic copper concentratio...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00107a045
更新日期：1991-03-01 00:00:00
abstract：:To eliminate an unwarranted metabolic pathway of the quinoline ring, a set of two compounds, where C-2 position of the antimalarial drug primaquine is blocked by metabolically stable bulky alkyl group are synthesized. Compound 2 [R = C(CH(3))(3)] of the series has produced excellent antimalarial efficacy against P. be...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0304562
更新日期：2004-01-15 00:00:00
abstract：:Production of the Gag-Pol polyprotein in human immunodeficiency virus (HIV) requires a -1 ribosomal frameshift, which is directed by a highly conserved RNA stem-loop. Building on our discovery of a set of disulfide-containing peptides that bind this RNA, we describe medicinal chemistry efforts designed to begin to und...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100231t
更新日期：2010-08-26 00:00:00
abstract：:Electrospray ionization mass spectrometry (ESI-MS) and tandem mass spectrometry (MS/MS) have been used for the first time to study the interaction of human alpha-thrombin with methyl 3-(2-methyl-1-oxopropoxy)[1]benzothieno[3,2-b]furan-2-carbox ylate (LY806303; 1), a potent and selective inhibitor whose mechanism of ac...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00068a012
更新日期：1993-08-06 00:00:00
abstract：:Novel 3,5-bis(benzylidene)-1-[3-(2-hydroxyethylthio)propanoyl]piperidin-4-ones (3a-e) display potent cytotoxicity and a preferential lethality toward various neoplasms compared to some normal cells. The corresponding sulfonic acid analogues 5a-e and an isostere 4 demonstrated substantially lower activity. The leads 3d...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101595p
更新日期：2011-05-12 00:00:00
abstract：:1,3-Dipolar cycloaddition of benzyl azide or peracetylated glucopyranosyl azides to propargyl halides or 1,4-dihalobutynes yielded 1-benzyl- or 1-glycosyl(halomethyl)-1,2,3-triazoles. Alkylating chloromethyl- bromomethyl- and iodomethyl-1,2,3-triazoles were also obtained from the corresponding hydroxymethyl derivative...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00191a007
更新日期：1979-05-01 00:00:00
abstract：:(R)-(-)- and (S)-(+)-alpha-methyl-beta-4-(fluorophenyl)-N-methyl-N- propynylethylamine [R)-(-)- and (S)-(+)-4-fluorodeprenyl) were synthesized via the reaction of 4-fluorobenzaldehyde with nitroethane followed by reduction with lithium aluminum hydride to produce racemic 4-fluoroamphetamine, which was resolved by recr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00169a034
更新日期：1990-07-01 00:00:00
abstract：:Matrix metalloprotease 12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been found in the lung of human COPD patients. MMP408 (14), a potent and selective MMP-12 inhibitor, was derived from a potent matrix metalloprotease 2 and 13 inhibitor via lead ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900093d
更新日期：2009-04-09 00:00:00
abstract：:A study of the hydrolysis of 30 substituted-phenyl hippurates by the enzyme ficin has been made. From the results the following quantitative structure--activity relationship (QSAR) has been derived: log 1/Km = 0.79 pi'3 + 0.58 sigma + 0.28 MR4,5 + 3.70. In this expression Km is the Michaelis constant, pi'3 refers to t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00377a009
更新日期：1984-11-01 00:00:00
abstract：:The scaffold concept was applied to systematically determine, analyze, and compare core structures of kinase inhibitors. From publicly available inhibitors of the human kinome, scaffolds and cyclic skeletons were systematically extracted and organized taking activity data, structural relationships, and retrosynthetic ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501237k
更新日期：2015-01-08 00:00:00
abstract：:The cardiotonic 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3- pyridazinyl)-2H-indol-2-one (1, LY195115) is a potent, competitive inhibitor (Ki = 80 nM) of sarcoplasmic reticulum derived phosphodiesterase (SR-PDE). Moreover, the compound is a potent positive inotrope both in vitro and in vivo. To assist furth...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00387a007
更新日期：1987-04-01 00:00:00
abstract：:The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00442
更新日期：2016-11-10 00:00:00
abstract：:Pyrazolo[3,4-d]pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being further optimized. Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo[3,4-d]pyrimidine prodrugs (1a-8a and 9a-e) with highe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00637
更新日期：2017-07-27 00:00:00
abstract：:The potent inhibitory activity of novel 2-benzyltetralone and 2-benzylidenetetralone derivatives vs liver microsomal retinoic acid metabolizing enzymes and a MCF-7 CYP26A1 cell assay is described. In the liver microsomal assay, the 2-biphenylmethyl-6-hydroxytetralone derivatives 16a and 16b were found to be potent inh...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0501681
更新日期：2005-11-17 00:00:00
abstract：:Certain structural similarities between prostaglandins with close-packed side chains and the perhydrocyclopentanophenanthrene nucleus of steroids prompted the synthesis and biological evaluation of 6beta, 17 beta-dihydroxy-5alpha-androstane-2alpha-carboxylic acid (30), its 6-deoxy derivative 28, and the corresponding ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00235a002
更新日期：1975-01-01 00:00:00
abstract：:This series of reports describe the development of orally active, highly potent, specific antagonists of the peptidoleukotrienes containing a (2-quinolinylmethoxy)phenyl moiety. The compounds reported in this paper contain an additional phenyl ring, which has significantly improved the receptor affinity. The effect of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00166a017
更新日期：1990-04-01 00:00:00
abstract：:We have previously determined that Ac-D-Trp-Leu-Asp-Ile-Ile-Trp (peptide I), an endothelin antagonist, binds specifically (Ki = 1.9 microM) to the rat pituitary gonadotropin-releasing hormone (GnRH) receptor. Moreover, peptide I exhibits a GnRH agonistic activity, mediated directly by the GnRH receptor. We now report ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990432o
更新日期：2000-07-27 00:00:00
abstract：:The preparation and activity against Plasmodium berghei of derivatives of 1-(4-methoxycinnamoyl)-4-(5-phenyl-4-oxo-2-oxazolin-2-yl)piperazine are described. Replacement of the cinnamoyl group was accomplished by acylation or alkylation of 1-(5-phenyl-4-oxo-2-oxazolin-2-yl)piperazine. Modifications of the 5-phenyl grou...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00246a009
更新日期：1975-12-01 00:00:00
abstract：:The synthesis of 19 (5-nitro-2,3-dihydro-1H-benzo[e]indol-1-yl)methyl sulfonate prodrugs containing sulfonate leaving groups and 7-substituted electron-withdrawing groups is reported. These were designed to undergo hypoxia-selective metabolism to form potent DNA minor groove-alkylating agents. Analogues 17 and 24, con...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm201717y
更新日期：2012-03-22 00:00:00
