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Chemical Biology & Drug Design

Cover image for Chemical Biology & Drug Design

August 2012

Volume 80, Issue 2

Pages i–iii, 155–347

  1. Issue Information

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

      Version of Record online: 16 JUL 2012 | DOI: 10.1111/j.1747-0285.2012.01434.x

  2. Reviews

    1. Top of page
    2. Issue Information
    3. Reviews
    4. Research Articles
    5. Research Letters
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      Antimalarial Drugs and Drug Targets Specific to Fatty Acid Metabolic Pathway of Plasmodium falciparum (pages 155–172)

      Tabish Qidwai and Feroz Khan

      Version of Record online: 28 MAY 2012 | DOI: 10.1111/j.1747-0285.2012.01389.x

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      Antimalarial drugs and pharmacophore against the targets specific to FASII of Plasmodium falciparum have been explored. In drug designing the host genetic factor must be consider. Polymorphisms in host and parasite genes and their role in drug response have been analyzed.

  3. Research Articles

    1. Top of page
    2. Issue Information
    3. Reviews
    4. Research Articles
    5. Research Letters
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      The Molecular Dynamics of Trypanosoma brucei UDP-Galactose 4′-Epimerase: A Drug Target for African Sleeping Sickness (pages 173–181)

      Aaron J. Friedman, Jacob D. Durrant, Levi C. T. Pierce, Thomas J. McCorvie, David J. Timson and J. Andrew McCammon

      Version of Record online: 2 MAY 2012 | DOI: 10.1111/j.1747-0285.2012.01392.x

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      Using molecular dynamics simulations, we investigate the atomistic motions of TbGalE in both the apo and holo states. The sampled conformations and protein dynamics depend not only on the presence of a UDP-sugar ligand, but also on the chirality of the UDP-sugar C4 atom. This dependence provides important insight into TbGalE function and may help guide future computer-aided drug-discovery efforts targeting this protein.

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      Generation of Receptor Structural Ensembles for Virtual Screening Using Binding Site Shape Analysis and Clustering (pages 182–193)

      David J. Osguthorpe, Woody Sherman and Arnold T. Hagler

      Version of Record online: 23 MAY 2012 | DOI: 10.1111/j.1747-0285.2012.01396.x

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      We apply a binding site shape overlap clustering method to crystal structures of CDK2 and HIV protease and show that ensembles of four cluster representative structures yield high enrichments and diverse actives. We then apply the method to an ensemble of androgen receptor generated with molecular dynamics and obtain results that are in agreement with those from the crystal structure ensembles. This work provides a step forward in the incorporation of protein flexibility into structure-based virtual screening.

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      Cysteinoyl- and Cysteine-containing Dipeptidoylbenzotriazoles with Free Sulfhydryl Groups: Easy Access to N-terminal and Internal Cysteine Peptides (pages 194–202)

      Tarek S. Ibrahim, Srinivasa R. Tala, Said A. El-Feky, Zakaria K. Abdel-Samii and Alan R. Katritzky

      Version of Record online: 14 MAY 2012 | DOI: 10.1111/j.1747-0285.2011.01303.x

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      Novel and stable N-protected, free sulfhydryl, cysteine-containing dipeptidoylbenzotriazoles formed internal cysteine containing N-protected free sulfhydryl tripeptides, tetrapeptides, and pentapeptide under mild reaction conditions in good yields that can be useful in the syntheses of other naturally occurring or biologically active cysteine-containing peptides.

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      The Chemical Tuning of a Weak Zinc Binding Motif for Histone Deacetylase Using Electronic Effects (pages 203–214)

      Patrick McCarren, Michelle L. Hall and Lewis Whitehead

      Version of Record online: 15 MAY 2012 | DOI: 10.1111/j.1747-0285.2012.01382.x

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      A small DFT model was used to predict improved zinc binding of an α-aminocarbonyl warhead for HDAC8 using structural knowledge and density functionals with an adequate treatment of dispersion interactions. Adding methyl groups increased electron donation to the metal and ligand binding and also increased beneficial desolvation.

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      Comparison of Dynamics of Extracellular Accesses to the β1 and β2 Adrenoceptors Binding Sites Uncovers the Potential of Kinetic Basis of Antagonist Selectivity (pages 215–226)

      Balaji Selvam, Jeff Wereszczynski and Irina G. Tikhonova

      Version of Record online: 2 MAY 2012 | DOI: 10.1111/j.1747-0285.2012.01390.x

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      The straight direction of selective antagonist unbinding, involving K347 as a H-bond translator is preferable in β1AR and the lateral (helices 5,6 and 7) direction of unbinding with the steering role of F194 and H296 is favourable in β2AR. Sequential binding of agonists and glycosylation to kinetic basis of ligand selectivity are discussed.

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      Syntheses and Structure–Activity Relationships of Seven Manganese–Salen Derivatives as Anti-amyloidogenic and Fibril-destabilizing Agents Against Hen Egg-white Lysozyme Aggregation (pages 227–236)

      Seifollah Bahramikia, Razieh Yazdanparast and Ali Gheysarzadeh

      Version of Record online: 2 MAY 2012 | DOI: 10.1111/j.1747-0285.2012.01391.x

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      In this research, we have studied the ability of several salen derivatives to inhibit amyloid self-assembly as well as to dissolve amyloid aggregates of hen egg-white lysozyme (HEWL), as an in vitro model system, with the aim of investigating their structure-activity relationships. Our results indicated that the aromatic rings of each salen derivative play the primary role in the aggregation inhibition and the side chain groups are responsible for enhancing or diminishing its behavior.

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      Synthesis and Potent In vitro Activity of Novel 1H-Benzimidazoles as Anti-MRSA Agents (pages 237–244)

      Hacer Karataş, Mehmet Alp, Sulhiye Yıldız and Hakan Göker

      Version of Record online: 30 APR 2012 | DOI: 10.1111/j.1747-0285.2012.01393.x

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      A new class of 1H-benzimidazolecarboxamidines were synthesized and evaluated for in vitro antibacterial and antifungal activities, including drug resistant bacterial strains. The most potent compound (32) has the same ratio of antiMRSA activity as Vancomycin (MIC100 = 0.78 μg/mL).

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      Design, Synthesis, and Antimycobacterial Property of PEG–bis(INH) Conjugates (pages 245–253)

      Dipti Kakkar, Anjani K. Tiwari, Krishna Chuttani, Alka Khanna, Anupama Datta, Harpal Singh and Anil K. Mishra

      Version of Record online: 30 MAY 2012 | DOI: 10.1111/j.1747-0285.2012.01394.x

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      Three poly(ethylene glycol) derivatives of Isoniazid have been designed and synthesized. Their biological evaluation has been carried out viz.-a-viz. antimycobacterial susceptibility, cytotoxicity, biodistribution, blood clearance and whole body imaging in infection models in rabbits. This study thoroughly discusses their pre-clinical evaluation with respect to the neat drug.

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      The N-terminal Region of CXCL11 as Structural Template for CXCR3 Molecular Recognition: Synthesis, Conformational Analysis, and Binding Studies (pages 254–265)

      Pasquale Palladino, Luigi Portella, Giovanni Colonna, Raffaele Raucci, Gabriella Saviano, Filomena Rossi, Maria Napolitano, Stefania Scala, Giuseppe Castello and Susan Costantini

      Version of Record online: 23 MAY 2012 | DOI: 10.1111/j.1747-0285.2012.01397.x

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      Since the inhibition of CXCR3 pathway was indicated as putative therapeutic target for the disease treatment, it is important to study what structural regions of CXCL11 interact with CXCR3 and what were the structural features. The obtained results indicate that the CXCL-11 N-terminal region can be considered as a good template of CXCR3/ligand recognition. Therefore the possibility of modifying the physico-chemical properties of the peptides can represent a good approach to improve the research for therapeutics of CXCR3-associated diseases.

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      p38β MAP Kinase as a Therapeutic Target for Pancreatic Cancer (pages 266–273)

      Abhay Kumar Singh, Roshan Pandey, Kamaldeep Gill, Ratnakar Singh, Anoop Saraya, Shyam S. Chauhan, Savita Yadav, Sujoy Pal, Nidhi Singh and Sharmistha Dey

      Version of Record online: 23 MAY 2012 | DOI: 10.1111/j.1747-0285.2012.01395.x

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      This study focused on development of P38β MAPK as a biological marker of pancreatic cancer, as this is an important component of intracellular signaling pathway that are activated in response to many extracellular stimuli leading to inflammatory response and eventually into cancer and was compared with the pancreatitic patients. In addition, we have designed and analysed the peptide inhibitor on the basis of the structure of ATP binding site of P38β and the known inhibitors.

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      Neuroprotective Effects of Vitexin, a Flavonoid, on Pentylenetetrazole-Induced Seizure in Rats (pages 274–278)

      Esmail Abbasi, Marjan Nassiri-Asl, Mahsa Shafeei and Mehdi Sheikhi

      Version of Record online: 23 MAY 2012 | DOI: 10.1111/j.1747-0285.2012.01400.x

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      Vitexin (5, 7, 4-trihydroxyflavone-8-glucoside), a flavonoid found in plants. The anticonvulsant effects of vitexin were investigated in rats. Vitexin affected minimal clonic seizures and generalized toni–clonic seizures induced by pentylenetetrazole.

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      A Strategy for Selective O6-Alkylguanine-DNA Alkyltransferase Depletion Under Hypoxic Conditions (pages 279–290)

      Philip G. Penketh, Krishnamurthy Shyam, Raymond P. Baumann, Kimiko Ishiguro, Eric V. Patridge, Rui Zhu and Alan C. Sartorelli

      Version of Record online: 23 MAY 2012 | DOI: 10.1111/j.1747-0285.2012.01401.x

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      In normal tissues high AGT levels block the toxicity O-6 position of guanine alkylating agents, whereas in tumor cells high AGT levels inhibit chemotherapeutic response. We have synthesized and characterized 2-nitro-6-benzyloxypurine, a prodrug of the potent AGT inhibitor O6-benzylguanine, designed to be selectively activated under the oxygen deficient conditions found only in solid tumors. 2-NBP depletes AGT activity in intact cells, and selectively sensitizes cells to the cytotoxic effects of laromustine strongly under oxygen deficient but not normoxic conditions.

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      Elucidation of Structure-activity Relationship of 2-Quinolone Derivatives and Exploration of Their Antitumor Potential Through Bax-induced Apoptotic Pathway (pages 291–299)

      Nitesh Kumar, Vasanth P. Raj, B. S. Jayshree, Sidhartha S. Kar, Arvind Anandam, Seeja Thomas, Prateek Jain, Amita Rai and C. M. Rao

      Version of Record online: 6 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01402.x

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      Nine 2-quinolone derivatives were screened for its in vitro cytotoxicity. Structural activity relationship has been studied based on lipophilicity and cytotoxicity of the molecules. nJST (1a) was found to be most effective among the compounds with lowest CTC50 value. Apoptosis was established by nuclear staining, DNA damage and gene expression. Acute toxicity study in mice indicates that the compound is safe till 2000 mg/kg. In vivo results using EAC model showed significant improvement in survival time.

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      Combined Pharmacophore and 3D-QSAR Study on A Series of Staphylococcus aureus Sortase A inhibitors (pages 300–314)

      Reaz Uddin, Mazhar U. Lodhi and Zaheer Ul-Haq

      Version of Record online: 11 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01403.x

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      Pharmacophore based 3D-QSAR studies were carried out on a series of rhodanine, pyridazinone and pyrazolethione analogs as SrtA inhibitors using GALAHAD

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      Molecular Docking and Dynamics Simulation, Receptor-based Hypothesis: Application to Identify Novel Sirtuin 2 Inhibitors (pages 315–327)

      Sugunadevi Sakkiah, Sundarapandian Thangapandian, Chanin Park, Minky Son and Keun W. Lee

      Version of Record online: 21 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01406.x

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      Molecular docking was carried out to form a complex-sirutin2 structure and subjected into molecular dynamics simulations. The dynamics hypothesis was generated using LigandScout and used in virtual screening. Finally 21 compounds were selected as a potent leads for SIRT2.

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      Identification of Novel Polo-like Kinase 1 Inhibitors by a Hybrid Virtual Screening (pages 328–339)

      Shuai Lu, Shan-Liang Sun, Hai-Chun Liu, Ya-Dong Chen, Hao-Liang Yuan, Yi-Ping Gao, Pei Yang and Tao Lu

      Version of Record online: 8 JUN 2012 | DOI: 10.1111/j.1747-0285.2012.01412.x

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      A combined ligand- and structure-based virtual screening was performed to identify novel PLK1 inhibitors. The most potent compounds showed an IC50 value of 6.99 μm against PLK1. The binding modes of two most potent compounds were studied by induced-fit docking.

  4. Research Letters

    1. Top of page
    2. Issue Information
    3. Reviews
    4. Research Articles
    5. Research Letters
    1. You have free access to this content
      Antimalarial Activity of Newly Synthesized Chalcone Derivatives In Vitro (pages 340–347)

      Neesha Yadav, Sandeep K. Dixit, Amit Bhattacharya, Lokesh C. Mishra, Manish Sharma, Satish K. Awasthi and Virendra K. Bhasin

      Version of Record online: 13 APR 2012 | DOI: 10.1111/j.1747-0285.2012.01383.x

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      Two step synthesis protocol was used to prepare twenty-seven chalcone analogs. Compound 9 (1-(4-benzoimidazol-1-yl-phenyl)-3-(2,4-dimethoxy-phenyl)-propen-1-one) was found to be most effective in inhibiting the growth of P. falciparum in vitro.

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