ZINC: a free tool to discover chemistry for biology. J Chem Inf Model

Department of Pharmaceutical Chemistry, Byers Hall, University of California San Francisco , 1700 Fourth St, Box 2550, San Francisco California 94158-2330, United States.
Journal of Chemical Information and Modeling (Impact Factor: 3.74). 05/2012; 52(7). DOI: 10.1021/ci3001277
Source: PubMed

ABSTRACT ZINC is a free public resource for ligand discovery.
The database contains over twenty million commercially available molecules
in biologically relevant representations that may be downloaded in
popular ready-to-dock formats and subsets. The Web site also enables
searches by structure, biological activity, physical property, vendor,
catalog number, name, and CAS number. Small custom subsets may be
created, edited, shared, docked, downloaded, and conveyed to a vendor
for purchase. The database is maintained and curated for a high purchasing
success rate and is freely available at

Download full-text


Available from: John J Irwin, Sep 26, 2015
1 Follower
91 Reads
    • "Energetically reduced zwitterion ligands were obtained from the Zinc database, (Irwin et al., 2012). AutoDock tools (Morris et al., 2009) were used to prepare molecules for hypothetical docking performed by AutoDock Vina (Trott and Olson, 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cys-loop GABA receptors represent important targets for human chemotherapeutics and insecticides and have potential as targets for novel anthelmintics (nematocides). However, compared to insect and mammalian receptors relatively little is known regarding the pharmacological characteristics of nematode cys-loop GABA receptors. Our aim was to investigate the agonist binding site of the cys-loop GABA receptor UNC-49 (Hco-UNC-49) from the parasitic nematode Haemonchus contortus. We used two-electrode voltage clamp electrophysiology to measure channel activation from classical GABA receptor agonists on Hco-UNC-49 expressed in Xenopus laevis oocytes. This was complimented with site-directed mutagenesis and in silico homology modeling. The sulphonated molecules P4S and taurine display no effect on Hco-UNC-49. Other classical cys-loop GABAA receptor agonists tested on the Hco-UNC-49B/C heteromeric channel had a rank order efficacy of GABA > TACA > Isoguvacine > IMA > R(-)-GABOB > S(+)-GABOB > GAA > Isonipecotic acid > DAVA (partial agonist) > β-alanine (partial agonist). In silico ligand docking also revealed some variation in binding between agonists. Mutagenesis of a key serine residue in binding loop C to threonine had minimal effects on GABA and IMA but significantly increased the maximal response of DAVA and caused a 2-fold decrease in the EC50 for R(-)-GABOB and S(+)-GABOB. Our data has revealed differences in the pharmacological profile of Hco-UNC-49 when compared to insect RDL and vertebrate cys-loop GABA receptors suggesting differences in the agonist binding pocket. These findings could possibly be exploited to develop new drugs that specifically target GABA receptors of parasitic nematodes. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 04/2015; 172(15). DOI:10.1111/bph.13158 · 4.84 Impact Factor
  • Source
    • "Instant JChem, a 2D similarity search tool from ChemAxon, was employed to search for structural analogs of 2-[(2-phenylethyl)sulfanyl]-1H-1,3-benzodiazole (compound 1). A similarity search was performed against the ZINC database v12.0 containing $18 million compounds (Irwin et al., 2012). All software parameters were set to their default values. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There has been a resurgence of interest in the development of androgen receptor (AR) inhibitors with alternative modes of action to overcome the development of resistance to current therapies. We demonstrated previously that one promising strategy for combatting mutation-driven drug resistance is to target the Binding Function 3 (BF3) pocket of the receptor. Here we report the development of a potent BF3 inhibitor, 3-(2,3-dihydro-1H-indol-2-yl)-1H-indole, which demonstrates excellent antiandrogen potency and anti-PSA activity and abrogates the androgen-induced proliferation of androgen-sensitive (LNCaP) and enzalutamide-resistant (MR49F) PCa cell lines. Moreover, this compound effectively reduces the expression of AR-dependent genes in PCa cells and effectively inhibits tumor growth in vivo in both LNCaP and MR49F xenograft models. These findings provide evidence that targeting the AR BF3 pocket represents a viable therapeutic approach to treat patients with advanced and/or resistant prostate cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Chemistry & biology 10/2014; 21(11):1476-1485. DOI:10.1016/j.chembiol.2014.09.012 · 6.65 Impact Factor
  • Source
    • "In additional to high-throughput screening and other conventional approaches, computer-aided drug design, guided by available protein structures in the Protein Data Bank (PDB) [25] and synthetic compounds from databases such as ZINC [26] can provide a cost-and time-effective strategy to search for new drug Fig. 2. A phylogenetic tree of NRs. A phylogenetic tree was constructed based on a multiple alignment of full-length protein sequences of all 48 NRs using Clustal Omega [12]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nuclear receptors (NRs), a family of 48 transcriptional factors, have been studied intensively for their roles in cancer development and progression. The presence of distinctive ligand binding sites capable of interacting with small molecules has made NRs attractive targets for developing cancer therapeutics. In particular, a number of drugs have been developed over the years to target human androgen- and estrogen receptors for the treatment of prostate cancer and breast cancer. In contrast, orphan nuclear receptors (ONRs), which in many cases lack known biological functions or ligands, are still largely under investigated. This review is a summary on ONRs that have been implicated in prostate and breast cancers, specifically retinoic acid-receptor-related orphan receptors (RORs), liver X receptors (LXRs), chicken ovalbumin upstream promoter transcription factors (COUP-TFs), estrogen related receptors (ERRs), nerve growth factor 1B-like receptors, and "dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1" (DAX1). Discovery and development of small molecules that can bind at various functional sites on these ONRs will help determine their biological functions. In addition, these molecules have the potential to act as prototypes for future drug development. Ultimately, the therapeutic value of targeting the ONRs may go well beyond prostate and breast cancers.
    Cancer Treatment Reviews 10/2014; 40(10). DOI:10.1016/j.ctrv.2014.10.005 · 7.59 Impact Factor
Show more