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Target-Focused Libraries from Otava

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December 2008 www.otavachemicals.com TARGET-FOCUSED LIBRARIES FROM OTAVA more information, quotes and ordering, please send an e-mail to [email protected] or [email protected] OTAVA, North American Division, 55 Ellerslie Ave., Suite 524, Toronto, ON, M2N 1X9, CANADA Tel.: 1-416-305-9979, Fax: 1-866-881-9921 (Toll-free in US & Canada) Target Focused Libraries Table of Contents Receptor-Based Target-Focused Libraries Building Receptor-Based Target-Focused Libraries 2 Human Protein Kinase CK2 Inhibitors: OTAVA's Approach in Action 4 Kinase Inhibitor Candidates ERK2 (Extracellular Signal-Regulated Kinase 2) 5 DAPK2 (Death-Associated Protein Kinase 2) 6 p38 MAPK (p38 MAP Kinase Alpha) 7 JAK2 (Janus Kinase 2) 8 PI3K (Phosphatidylinositol 3-Kinase) 9 PDK-1 (3-Phosphoinositide-Dependent Kinase-1) 10 CDK2 (Cyclin-Dependent Kinase 2) 11 GSK3 (Glycogen Synthase Kinase-3) 12 FGFR1K (Fibroblast Growth Factor Receptor 1 Tyrosine Kinase) 13 PKA (cAMP-Dependent Protein Kinase) 14 AURKB (Aurora B Kinase) 15 VEGFR2 (Vascular Endothelial Growth Factor Receptor-2 Kinase) 16 Hydrolase Inhibitor Candidates Acetylcholinesterase 17 Phospholipase A2 18 Other Inhibitor Candidates Estrogen Receptor 19 Receptor-Based Target-Focused Libraries: Preparation on request List of OTAVA's Receptor-Based Target-Focused Libraries you may request for 22 Ligand-Based Target-Focused Libraries Building Ligand-Based Target-Focused Libraries 24 List of OTAVA's Ligand-Based Target-Focused Libraries 26 Ligand-Based Target-Focused Libraries (EXAMPLES) Lipid Signaling Inhibitor Candidates 34 Phosphorylation/Dephosphorylation Inhibitor Candidates 35 Phosphodiesterase Inhibitor Candidates 36 Protease inhibitors 37 Reductase inhibitors 38 For more information please send an e-mail to [email protected] or, for quotes and ordering, to [email protected] OTAVA - North American Division: 15 Dundonald St., Suite 1902, Toronto, ON, M4Y 1K4, Canada; Tel.: 1-416-305-9979, Fax: 1-866-881-9921 (Toll-free in US & Canada) Target Focused Libraries Receptor-Based Target-Focused Libraries For more information please send an e-mail to [email protected] or, for quotes and ordering, to [email protected] OTAVA - North American Division: 15 Dundonald St., Suite 1902, Toronto, ON, M4Y 1K4, Canada; Tel.: 1-416-305-9979, Fax: 1-866-881-9921 (Toll-free in US & Canada) 1 Receptor-Based Target-Focused Libraries OTAVA's Approach Building Receptor-Based Target-Focused Libraries During the early stages of drug development, it is often necessary to perform in silico screening of large numbers of small molecules. The aim is to find the most active members from a stock collection that are to be subjected to in vitro evaluation. The result is a library of molecules that possesses significant activity. The quality of the library, however, can only be as good as the screening method used. It is quality that OTAVA wants to bring to its customers. Our Receptor-Based Target-Focused libraries are created from an extensive stock collection, and a rigorous process of refinement that involves harnessing the most current methods of theoretical medicinal chemistry. Design of Receptor-Based focused libraries. OTAVA's Receptor-Based Target-Focused This approach was employed for each of libraries are generated through a unique OTAVA’s Receptor-Based Target-Focused libraries. approach. First, the stock collection is filtered according to the Lipinski and Veber rules: CLogP from 0 to 5 MW from 160 to 500 number of H-donors from 0 to 5 number of H-acceptors from 0 to 9 number of NO2 groups from 0 to 2 number of rotatable bonds from 0 to 10 For more information please send an e-mail to [email protected] or, for quotes and ordering, to [email protected] OTAVA - North American Division: 15 Dundonald St., Suite 1902, Toronto, ON, M4Y 1K4, Canada; Tel.: 1-416-305-9979, Fax: 1-866-881-9921 (Toll-free in US & Canada) 2 Receptor-Based Target-Focused Libraries OTAVA's Approach Building Receptor-Based Target-Focused Libraries, continued OTAVA's approach uses Sharp Focusing: each molecule's interaction is measured with only a single target in a protein family. The target's X-ray crystallography data is thus incorporated. Next, after preprocessing, the molecules are individually docked. Flexible molecular docking is the core of OTAVA's approach. After docking the ligand, a re-scoring algorithm is applied. This re-scoring procedure involves correcting the final summation of interaction Ligand in Aurora B active site. energies (the score) according to the ligand's Docking example from the OTAVA Aurora structural features. B Kinase Receptor-Based Target-Focused Finally, each docking complex is scanned for key library. contacts: H-bonds formed between the ligand and The detection of H-bonds between the critical amino acid residues in the protein's active ligand and a key Aurora B residue site. This detailed analysis of each docked (Ala173) was used in preparation of the library. protein-ligand complex is critical to OTAVA's approach. Our libraries, created this way, are expected to have a higher probability of interacting with potential drug targets. All of the Receptor-Based Target-Focused libraries in this catalogue are available upon request, and come with docking scores and values for drug-like properties. For more information please send an e-mail to [email protected] or, for quotes and ordering, to [email protected] OTAVA - North American Division: 15 Dundonald St., Suite 1902, Toronto, ON, M4Y 1K4, Canada; Tel.: 1-416-305-9979, Fax: 1-866-881-9921 (Toll-free in US & Canada) 3 Receptor-Based Target-Focused Libraries OTAVA's Approach Human Protein Kinase CK2 Inhibitors: OTAVA's Approach in Action Protein kinase CK2 is a molecule that participates in the development of some cancers, viral infections and inflammatory failures. As such, small organic inhibitors of CK2, besides application in scientific research, may have therapeutic significance. In our recent Journal of Medicinal Chemistry paper (see ref. below) we presented a new class of CK2 inhibitors: 3-carboxy-4(1H)-quinolones. This class of inhibitors was discovered through receptor-based virtual screening of the OTAVA 70,000-compound library. According to theoretical calculations and 3D representation of the structural experimental data, a structural model describing the model that characterizes binding key features of 3-carboxy-4(1H)-quinolones features of the inhibitors (A) and (B). responsible for tight binding to the CK2 active site The most important intermolecular and was developed. Docking and molecular dynamics intramolecular hydrogen bonds are represented as dashed lines. The CK2 studies allowed us to propose a binding mode in amino acid residues involved in key which the key interactions were hydrogen bonds hydrophobic interactions with the ligand between the ligand's 3-carboxy group and the two are indicated as well. residues (Lys68 and Asp175) in the CK2 ATP-binding cleft, as well as hydrophobic contacts with Val66, Ile174, and Phe113. The resulting model correlated well with X-ray data for the complex CK2-IQA. It was revealed that the most active compounds — 5,6,8-trichloro-4-oxo-1,4-dihydroquinoline-3- carboxylic acid (A) (IC = 0.3 µM) and 4-oxo-1,4- Ref.: Evaluation of 3-Carboxy-4(1H)-quinolones as 50 Inhibitors of Human Protein Kinase CK2. dihydrobenzo[h]quinoline-3-carboxylic acid (B) (IC50 Golub, A.G., Yakovenko, O.Ya., Bdzhola, = 1 µM) — were ATP competitive (K values were V.G., Sapelkin, V.M., Zien, P., and Yarmoluk, i S.M. J. Med. Chem., 2006, 10.1021/jm050048t 0.06 and 0.28 µM, respectively). In vitro evaluation of http://dx.doi.org/10.1021/jm050048t the inhibitors on seven protein kinases demonstrated considerable selectivity toward CK2. For more information please send an e-mail to [email protected] or, for quotes and ordering, to [email protected] OTAVA - North American Division: 15 Dundonald St., Suite 1902, Toronto, ON, M4Y 1K4, Canada; Tel.: 1-416-305-9979, Fax: 1-866-881-9921 (Toll-free in US & Canada) 4 Receptor-Based Target-Focused Libraries Kinase Inhibitors Extracellular Signal- NEW! Regulated Kinase 2 Extracellular signal-regulated kinase 2 (ERK2) has become an attractive target for the development of therapeutics for the treatment of cancer. Eight new inhibitors of ERK2 by means of a drug design protocol involving the virtual screening with docking simulations and in vitro enzyme assay were recently identified. The newly discovered inhibitors can be categorized into three structural classes and reveal a significant potency with IC50 values ranging from 1 to 30 μM. Ref.: Park H, Bahn YJ, Jeong DG, Woo EJ, Kwon JS, Ryu SE. Identification of novel inhibitors of extracellular signal-regulated kinase 2 based on the structure-based virtual screening. Bioorg Med Chem Lett. 2008 Oct 15;18(20):5372-6. Number of Product Description Target Source Input Libraries Compounds Extracellular Signal- 2053 Extracellular Homo sapiens OTAVA Stock Collection Regulated Kinase 2 Signal-Regulated + Life Chemicals Stock focused library Kinase 2 Collection 500,000 compounds For more information please send an e-mail to [email protected] or, for quotes and ordering, to [email protected] OTAVA - North American Division: 15 Dundonald St., Suite 1902, Toronto, ON, M4Y 1K4, Canada; Tel.: 1-416-305-9979, Fax: 1-866-881-9921 (Toll-free in US & Canada) 5 Receptor-Based Target-Focused Libraries Kinase Inhibitors Death-Associated Protein Kinase 2 Death associated protein kinase (DAPK) is a calmodulin (CaM)-regulated serine/threonine protein kinase implicated in diverse apoptosis pathways, including those involved in neuronal cell death and tumour suppression. The requirement of DAPK catalytic activity for its proposed cell functions and the validation of protein kinases as therapeutic targets demand that DAPK be examined as a potential therapeutic target in human disease. The current body of knowledge raises the possibility of DAPK as a therapeutic target for diseases characterised by rapid neurodegeneration, such as stroke or traumatic brain injury.
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  • A New Computational Approach to Evaluating Systemic Gene–Gene Interactions in a Pathway Affected by Drug LY294002

    A New Computational Approach to Evaluating Systemic Gene–Gene Interactions in a Pathway Affected by Drug LY294002

    processes Article A New Computational Approach to Evaluating Systemic Gene–Gene Interactions in a Pathway Affected by Drug LY294002 Shinuk Kim College of Kyedang General Education, Sangmyung University, Cheonan 31066, Korea; [email protected]; Tel.: +82-(41)-550-5452; Fax: +82-(41)-550-5439 Received: 14 August 2020; Accepted: 23 September 2020; Published: 1 October 2020 Abstract: In this study, we investigate how drugs systemically affect genes via pathways by integrating information from interactions between chemical compounds and molecular expression datasets, and from pathway information such as gene sets using mathematical models. First, we adopt drug-induced gene expression datasets; then, employ gene set enrichment analysis tools for selecting candidate enrichment pathways; and lastly, implement the inverse algorithm package for identifying gene–gene regulatory networks in a pathway. We tested LY294002-induced datasets of the MCF7 breast cancer cell lines, and found a CELL CYCLE pathway with 101 genes, ERBB signaling pathway consisting of 82 genes, and MTOR pathway consisting of 45 genes. We consider two interactions: quantity strength depending on number of interactions, and quality strength depending on weight of interaction as positive (+) and negative ( ) interactions. Our methods revealed ANAPC1-CDK6 ( 0.412) and − − ORC2L- CHEK1(0.951) for the CELL CYCLE pathway; INS-RPS6 ( 3.125) and PRKAA2-PRKAA2 − (+1.319) for the MTOR pathway; and CBLB-RPS6KB1 ( 0.141), RPS6KB1-CBLC (+0.238) for the ERBB − signaling pathway to be top quality interactions. Top quantity interactions discovered include 12; the CDC ( ,+) gene family for the CELL CYCLE pathway, 20; PIK3 ( ), 23; PIK3CG (+) for the MTOR − − pathway, 11; PAK ( ), 10; PIK3 (+) for the ERBB signaling pathway.
  • Gene Expression Profiling of Micrornas Associated with UCA1 in Bladder Cancer Cells

    Gene Expression Profiling of Micrornas Associated with UCA1 in Bladder Cancer Cells

    INTERNATIONAL JOURNAL OF ONCOLOGY 48: 1617-1627, 2016 Gene expression profiling of microRNAs associated with UCA1 in bladder cancer cells XIAOJUAN XIE1,2, JINGJING PAN1, LIQIANG WEI2, SHOUZHEN WU3, HUILIAN HOU4, XU LI3 and WEI CHEN1 1Department of Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061; 2Shaanxi Center for Clinical Laboratory, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068; 3Center for Translational Medicine, 4Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China Received November 11, 2015; Accepted December 27, 2015 DOI: 10.3892/ijo.2016.3357 Abstract. Emerging evidence indicates that non-coding and positively correlated with miR-196a, whereas UCA1 and RNAs, such as lncRNAs and microRNAs, play important miR-196a were negatively correlated with p27kip1, which was roles in diverse diseases, such as cancer, immune diseases downregulated in bladder cancer patients. Thus, our findings and cardiovascular diseases. Interestingly, lncRNAs could provided valuable information on miRNAs associated with directly or indirectly regulate the expression of miRNAs. UCA1 in bladder cancer, which could be helpful to further However, the expression profiling of miRNAs associated with explore the related genes and molecular networks fundamental UCA1 in bladder cancer remains unknown. Here, we used in bladder cancer progression. Illumina deep sequencing to sequence miRNA libraries from both the UCA1 knockdown and normal high-expression 5637 Introduction cells. We identified 225 and 235 miRNAs expressed in 5637 cells of normal high-expression and knockdown of UCA1, Recently, emerging studies have demonstrated that 70-90% of respectively.