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Chemical Biology & Drug Design

Cover image for Chemical Biology & Drug Design

September 2012

Volume 80, Issue 3

Pages i–iii, 349–488

  1. Issue Information

    1. Top of page
    2. Issue Information
    3. Research Articles
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      Issue Information (pages i–iii)

      Version of Record online: 23 JUL 2012 | DOI: 10.1111/j.1747-0285.2012.01445.x

  2. Research Articles

    1. Top of page
    2. Issue Information
    3. Research Articles
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      Conformation-specific Display of 4E10 and 2F5 Epitopes on Self-assembling Protein Nanoparticles as a Potential HIV Vaccine (pages 349–357)

      Newton Wahome, Tanya Pfeiffer, Ina Ambiel, Yongkun Yang, Oliver T. Keppler, Valerie Bosch and Peter Burkhard

      Version of Record online: 3 JUL 2012 | DOI: 10.1111/j.1747-0285.2012.01423.x

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      We use our self-assembling protein nanoparticle (SAPN) as an antigen presenting system display the HIV-MPER epitopes 4E10 and 2F5 epitope in a conformation specific manner. Rats were immunized with MPER-SAPNs and their sera were analyzed for induced humoral anti-HIV-1 responses. We show that high MPER-specific titers can be raised via the repetitive antigen display of MPER on the SAPN without the need for adjuvant.

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      LigMerge: A Fast Algorithm to Generate Models of Novel Potential Ligands from Sets of Known Binders (pages 358–365)

      Steffen Lindert, Jacob D. Durrant and J. Andrew McCammon

      Version of Record online: 27 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01414.x

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      A novel automated, ligand-based algorithm ‘LigMerge’ for systematically ‘swapping’ the chemical moieties of known ligands in order to generate novel ligands with potentially improved potency has been developed. LigMerge identifies the maximum common substructure of two three-dimensional ligand models, and then systematically mixes and matches the distinct fragments attached to the common substructure at each common atom, thereby generating multiple compound models related to the known inhibitors that can be evaluated using computer docking prior to synthesis and experimental testing.

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      Discovery of Novel Bruton’s Tyrosine Kinase Inhibitors Using a Hybrid Protocol of Virtual Screening Approaches Based on SVM Model, Pharmacophore and Molecular Docking (pages 366–373)

      Hua-Lin Wan, Ze-Rong Wang, Lin-Li Li, Chuan Cheng, Pan Ji, Jing-Jing Liu, Hui Zhang, Jun Zou and Sheng-Yong Yang

      Version of Record online: 27 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01415.x

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      Bruton’s tyrosine kinase (BTK) has emerged as a potential target for the treatment of B-cell malignancies and autoimmune diseases. We introduced a hybrid protocol of virtual screening (VS) methods including support vector machine model-based VS (SB-VS), pharmacophore model-based (PB-VS), and docking-based VS (DB-VS) for retrieving new BTK inhibitors from commercially available chemical databases. Thirty-nine compounds were selected from the final hits and have been shifted to the subsequent experimental studies.

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      Enhancing and Limiting Endothelin-1 Signaling with a Cell-penetrating Peptide Mimicking the Third Intracellular Loop of the ETB Receptor (pages 374–381)

      Christine O. Sallum, Jamie L. Wilson, Chamila Rupasinghe, Eric Berg, Jun Yu, Daniel S. Green, Linda Taylor, Dale Mierke and Peter Polgar

      Version of Record online: 27 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01405.x

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      A peptide consisting of the cell-permeable peptide, TAT, linked to the intracellular third loop of the endothelin-1 (ET-1) type B receptor (ETB) was synthesized and investigated for its ability to modulate ETB receptor activity. In CHO cells transfected with the human ETB receptor, the peptide suppressed ET-1 activation. In the normal human pulmonary artery smooth muscle cells (hPASMCs), the peptide enhanced ERK activation by ET-1 slightly but it markedly enhanced the ET-1 activation of ERK in the BMP2R mutant hPASMCs.

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      Synthesis and Biological Evaluation of Triazole Derivatives as Potential Antifungal Agent (pages 382–387)

      Xiaoyun Chai, Guang Yang, Jun Zhang, Shichong Yu, Yan Zou, Qiuye Wu, Dazhi Zhang, Yuanying Jiang, Yongbing Cao and Qingyan Sun

      Version of Record online: 27 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01398.x

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      A series of triazole antifungal agents with piperidine side chains were synthesized. And a molecular model for the binding between compound 12 and the active site of CACYP51 was provided based on the computational docking results.

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      Synthesis and In Vitro Antibacterial Activity of Novel 3-Azabicyclo[3.3.0]octanyl Oxazolidinones (pages 388–397)

      Deepak Bhattarai, Sun H. Lee, Seon H. Seo, Ghilsoo Nam, Soon B. Kang, Ae N. Pae, Eunice E. Kim, Taegwon Oh, Sang-Nae Cho and Gyochang Keum

      Version of Record online: 27 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01404.x

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      We synthesized a series of oxazolidinone-type antibacterials in which morpholine C-ring of linezolid has been modified by substituted 3-azabicyclo[3.3.0]octanyl rings, and acetamide or 1,2,3-triazole heterocycle was used as C-5 side chain of oxazolidinone. Several analogs in this series exhibited potent in vitro antibacterial activity comparable or superior to linezolid against panel of susceptible and resistant Gram-positive, Gram-negative bacteria and Mycobacterium tuberculosis (Mtb). Compounds 10a, 10b, 11a, and 15a displayed highly potent activity against M. tuberculosis.

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      Novel Cruzain Inhibitors for the Treatment of Chagas’ Disease (pages 398–405)

      Kathleen E Rogers, Henrik Keränen, Jacob D. Durrant, Joseline Ratnam, Allison Doak, Michelle R. Arkin and J. Andrew McCammon

      Version of Record online: 27 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01416.x

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      Trypanosoma cruzi, the etiological agent of Chagas’ disease, affects millions of individuals and current therapies are inadequate. Using an exhaustive virtual-screening and experimental-validation approach, we identify several small-molecule inhibitors of cruzain, an essential cysteine protease of the protozoan parasite T. cruzi. Optimization of these chemical scaffolds could lead to the development of direly needed novel drugs useful in the treatment of Chagas’ disease.

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      Prediction of Organ Toxicity Endpoints by QSAR Modeling Based on Precise Chemical-Histopathology Annotations (pages 406–416)

      Eugene Myshkin, Richard Brennan, Tatiana Khasanova, Tatiana Sitnik, Tatiana Serebriyskaya, Elena Litvinova, Alexey Guryanov, Yuri Nikolsky, Tatiana Nikolskaya and Svetlana Bureeva

      Version of Record online: 27 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01411.x

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      Annotated compound-toxicity associations defined histologically from rat and mouse experiments were used to build quantitative structure-activity relationship models predicting subcategories of liver and kidney toxicity: liver necrosis, liver relative weight gain, liver lipid accumulation, nephron injury, kidney relative weight gain, and kidney necrosis. All models were validated using two independent test sets and demonstrated overall good performance: initial validation showed 0.80–0.96 sensitivity (correctly predicted toxic compounds) and 0.85–1.00 specificity (correctly predicted non-toxic compounds).

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      Synthetic Biotinylated Peptide Compound, BP21, Specifically Recognizes Lysophosphatidylcholine Micelles (pages 417–425)

      Akira Sato, Junken Aoki and Keiichi Ebina

      Version of Record online: 3 JUL 2012 | DOI: 10.1111/j.1747-0285.2012.01413.x

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      The interaction between synthetic biotinylated peptide compound, BP21, and lysophosphatidylcholine (LPC) was assessed by using fluorescence spectroscopy, polyacrylamide gel electrophoresis, and surface plasmon resonance. These results indicate that BP21 specifically recognizes LPC micelles, which are implicated in many inflamatory diseases. Further study of the interaction between BP21 and LPC micelles may provide important information for the prevention and treatment of many inflammatory diseases caused LPC micelles.

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      Discovery, Synthesis and Evaluation of Novel Cholesterol Absorption Inhibitors (pages 426–433)

      Xiaoyun Zhu, Jianfeng Ji, Dandan Huang, Yan Zhu, Chunlei Tang, Xuan Yang, Hai Qian and Wenlong Huang

      Version of Record online: 27 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01421.x

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      Two classes of novel substituted oxazolidinones were identified by virtual screening as the candidates of cholesterol absorption inhibitors to treat coronary artery disease. All compounds demonstrated effect of different degrees in lowering the total cholesterol in serum. Interestingly, compounds 2a–2f appeared to have the moderate potential to lower triglyceride levels, which were superior to that of normal cholesterol absorption inhibitors including ezetimibe.

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      Anti-Inflammatory Property of n-Hexadecanoic Acid: Structural Evidence and Kinetic Assessment (pages 434–439)

      Vasudevan Aparna, Kalarickal V. Dileep, Pradeep K. Mandal, Ponnuraj Karthe, Chittalakkottu Sadasivan and Madathilkovilakathu Haridas

      Version of Record online: 27 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01418.x

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      Investigations were done to identify the mode of inhibition of PLA2 by the n-hexadecanoic acid. The enzyme kinetics study and analysis of crystal structure proved that n-hexadecanoic acid inhibits PLA2 in a competitive manner. The inferences from the present study validate the rigorous use of medicated oils rich in n-hexadecanoic acid for the treatment of rheumatic symptoms in the traditional medical system of India, Ayurveda.

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      Identifying the Molecular Mechanics and Binding Dynamics Characteristics of Potent Inhibitors to HIV-1 Protease (pages 440–454)

      Dechang Li, Ming S. Liu, Baohua Ji, Keh-Chih Hwang and Yonggang Huang

      Version of Record online: 27 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01417.x

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      Correlation between the association rate constant and the radius of gyration of inhibitors. The dash black lines is the trend line and the dash red circle highlights the confined region of FDA-approved inhibitors (solid pink-color dots). The inset shows the interaction between the inhibitor and the PR during the binding process.

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      Modeling the Binding Affinity of p38α MAP Kinase Inhibitors by Partial Least Squares Regression (pages 455–470)

      Nikita Basant, Caterina Durante, Marina Cocchi and M. Cristina Menziani

      Version of Record online: 28 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01419.x

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      Partial Least Squares regression was used to develop a Quantitative Structure Activity Relationship (QSAR) model to predict the binding affinities of p38α MAP kinase inhibitors. The selected model successfully predicted the test set with a Root Mean Square Error of Prediction of 1.36. The regression coefficients and the Variable Importance in Projection plots highlighted the residue-inhibitor interactions which exhibited largest absolute effect on the ligand binding

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      The Molecular Design of S-Nitrosothiols as Photodynamic Agents for Controlled Nitric Oxide Release (pages 471–478)

      Niroshini M. Giles, Sweta Kumari, Bevan P. Gang, Chun W. W. Yuen, Emilie M. F. Billaud and Gregory I. Giles

      Version of Record online: 28 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01420.x

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      We designed photoactive S-nitrosothiol drugs that release nitric oxide (NO) upon irradiation. These drugs have improved NO release kinetics compared to currently available S-nitrosothiols, with major changes in half-life a function of the intensity or duration of the photostimulus. Cytotoxicity studies confirmed that light could be used as a trigger mechanism to induce cell death, indicating that the molecules are promising candidates for both chemical biology approaches to investigate NO signaling and clinical photodynamic therapy.

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      Synthesis and Biological Evaluation of Oral Prodrugs Based on the Structure of Gemcitabine (pages 479–488)

      Cuirong Zhao, Xiaoxia Xue, Gang Li, Cuicui Sun, Changjun Sun, Xianjun Qu and Wenbao Li

      Version of Record online: 25 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01422.x

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      A series of oral prodrugs based on the structure of gemcitabine were synthesized. Physiological and metabolic stabilities, pharmacokinetics and antitumor activities were evaluated for representative compounds.

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