Chemical Biology & Drug Design

Cover image for Chemical Biology & Drug Design

August 2011

Volume 78, Issue 2

Pages i–iii, 191–321

  1. Issue Information

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

      Article first published online: 13 JUL 2011 | DOI: 10.1111/j.1747-0285.2011.01165.x

  2. Research Articles

    1. Top of page
    2. Issue Information
    3. Research Articles
    4. Research Letters
    1. You have full text access to this OnlineOpen article
      Pyrone-Based Inhibitors of Metalloproteinase Types 2 and 3 May Work as Conformation-Selective Inhibitors (pages 191–198)

      Jacob D. Durrant, César A. F. de Oliveira and J. Andrew McCammon

      Article first published online: 20 JUN 2011 | DOI: 10.1111/j.1747-0285.2011.01148.x

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      We here investigate the predicted binding modes and energies of known MMP inhibitors docked into multiple structures extracted from MD simulations. Our findings suggest that accounting for protein dynamics is essential for the accurate prediction of binding affinity and selectivity.

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      Chemogenetic Analysis of Human Protein Methyltransferases (pages 199–210)

      Victoria M. Richon, Danielle Johnston, Christopher J. Sneeringer, Lei Jin, Christina R. Majer, Keith Elliston, L. Fred Jerva, Margaret Porter Scott and Robert A. Copeland

      Article first published online: 16 JUN 2011 | DOI: 10.1111/j.1747-0285.2011.01135.x

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      Ligand affinity map for the S-adenosylmethionine (SAM) utilization by human protein methyltransferases. The value of SAM KM is inversely proportional to the diameter of the red spheres associated with each enzyme.

    3. Targeting Metalloproteins by Fragment-Based Lead Discovery (pages 211–223)

      Sherida Johnson, Elisa Barile, Biancamaria Farina, Angela Purves, Jun Wei, Li-Hsing Chen, Sergey Shiryaev, Ziming Zhang, Irina Rodionova, Arpita Agrawal, Seth M. Cohen, Andrei Osterman, Alex Strongin and Maurizio Pellecchia

      Article first published online: 16 JUN 2011 | DOI: 10.1111/j.1747-0285.2011.01136.x

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      We describe a novel fragment based drug discovery approach using a metal targeting fragment library. The library is based on a variety of distinct classes of metal-binding groups designed to reliably anchor the fragments at the target’s metal ions. We demonstrate that the approach can effectively identify novel, potent and selective agents that can be readily natured into lead molecules for metalloprotein-targeted therapeutics.

    4. Comprehensive Analysis of Single- and Multi-Target Activity Cliffs Formed by Currently Available Bioactive Compounds (pages 224–228)

      Anne M. Wassermann, Dilyana Dimova and Jürgen Bajorath

      Article first published online: 24 JUN 2011 | DOI: 10.1111/j.1747-0285.2011.01150.x

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      A systematic analysis of single- and multi-target activity cliffs contained in currently available collections of bioactive compounds is reported. The distribution of large-magnitude activity cliffs over different target families, the target selectivity of cliff-forming compounds, and the polypharmacological nature of multi-target activity cliffs was studied.

    5. Novel Chiral Skeletons for Drug Discovery: Antibacterial Tetramic Acids (pages 229–235)

      Chloe A. Holloway, Christopher J. Matthews, Yong-Chul Jeong, Mark G. Moloney, Christine F. Roberts and Muhammad Yaqoob

      Article first published online: 16 JUN 2011 | DOI: 10.1111/j.1747-0285.2011.01133.x

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      Chiral tetramates are useful chiral fragments which may be used to generate libraries with antibacterial activity.

    6. Optimizing QSAR Models for Predicting Ligand Binding to the Drug-Metabolizing Cytochrome P450 Isoenzyme CYP2D6 (pages 236–251)

      Marilena Saraceno, Ilaria Massarelli, Marcello Imbriani, Thomas L. James and Anna M. Bianucci

      Article first published online: 14 JUN 2011 | DOI: 10.1111/j.1747-0285.2011.01137.x

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      The cytochrome P450 isozyme CYP2D6 plays a crucial role in establishing in vivo drug levels, especially in multidrug regimens. The current study aimed to develop reliable predictive QSAR models for estimating the CYP2D6 inhibition properties of drug candidates.

    7. Assessing Protein Kinase Selectivity with Molecular Dynamics and MM-PBSA Binding Free Energy Calculations (pages 252–259)

      Elena Muzzioli, Alberto Del Rio and Giulio Rastelli

      Article first published online: 13 JUN 2011 | DOI: 10.1111/j.1747-0285.2011.01140.x

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      An application of molecular dynamics (MD) and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) techniques to the prediction of protein kinase inhibitor selectivity is presented. The free energies of binding of a potent and selective ERK2 inhibitor were computed from 15 ns fully solvated MD simulations of the ERK2, SRC, LCK, GSK3, JNK3 and Aurora-A complexes. The results show correlation with experimentally-determined selectivities and provide useful insights into the underlying structural determinants for selectivity

    8. Interaction Between the Antibiotic Tetracycline and the Elongation Factor 1α from the Archaeon Sulfolobus solfataricus (pages 260–268)

      Anna Lamberti, Nicola M. Martucci, Immacolata Ruggiero, Paolo Arcari and Mariorosario Masullo

      Article first published online: 16 JUN 2011 | DOI: 10.1111/j.1747-0285.2011.01142.x

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      Archaeal Sulfolobus solfataricus elongation factor 1α interacts with the eubacterial antibiotic tetracycline. The effects produced on engineered forms of SsEF-1α indicate that the M-domain is essential for the interaction; the main effect of the antibiotic is exerted on the GTP-bound form of the enzyme. Tetracycline renders SsEF-1α slightly less stable against heat inactivation. This behaviour can be attributed to a reduced energy of activation of the heat inactivation process.

    9. Transformations of 3-Hydroxy Steroids with Lewis and Anhydrous Protic Acids: The Case of Pregn-4-en-3β,17α,20β-Triol (pages 269–276)

      Rosaria De Marco, Antonella Leggio, Angelo Liguori, Francesca Perri and Carlo Siciliano

      Article first published online: 13 JUN 2011 | DOI: 10.1111/j.1747-0285.2011.01147.x

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      Pregn-4-en-3β,17α,20β-triol generates only pregn-3,5-dien-17α,20β-diol by treatment with Lewis acids. Pregn-4-en-3β,17α,20β-triol is converted into a 3:2 mixture of pregn-3,5-dien-17α,20β-diol and its 17β epimer upon anhydrous protic acid catalysis

    10. Diagnostic Value of Anti-GBV-C Antibodies in HIV-Infected Patients (pages 277–282)

      Maria J. Gómara, Leticia Fernández, Teresa Pérez, Solveig Tenckhoff, Aurora Casanovas, Hans L. Tillmann and Isabel Haro

      Article first published online: 20 JUN 2011 | DOI: 10.1111/j.1747-0285.2011.01143.x

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      The presence of antibodies against chimeric peptides formed by two domains of different GBV-C proteins could represent a good marker of exposure to GBV-C in HIV patients.

    11. Insights into the Structural Requirements of PKCβII Inhibitors Based on HQSAR and CoMSIA Analyses (pages 283–288)

      Hirdesh Kumar, Rajendra Kumar, Baljinder K. Grewal and M. Elizabeth Sobhia

      Article first published online: 20 JUN 2011 | DOI: 10.1111/j.1747-0285.2011.01144.x

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      A combined 2-D and 3-D QSAR study on a set of maleimide derivatives as inhibitor of PKCβII was performed by HQSAR and CoMSIA analysis to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The findings will be useful in development of novel and potential PKCβII inhibitors

    12. Discovery of Potential Integrin VLA-4 Antagonists Using Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies (pages 289–300)

      Sundarapandian Thangapandian, Shalini John, Sugunadevi Sakkiah and Keun Woo Lee

      Article first published online: 20 JUN 2011 | DOI: 10.1111/j.1747-0285.2011.01127.x

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      Highly reliable pharmacophore model was developed for VLA-4 antagonists. A set of database hits were docked into the active site of homology modeled VLA-4 to filter the promising lead compounds for future drug design. Novelty of the leads was also confirmed.

    13. Integrating In Silico and In vitro Approaches to Dissect the Stereoselectivity of Bacillus subtilis Lipase A toward Ketoprofen Vinyl Ester (pages 301–308)

      Zhong Ni, Peng Zhou, Xin Jin and Xian-Fu Lin

      Article first published online: 24 JUN 2011 | DOI: 10.1111/j.1747-0285.2011.01097.x

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      Is it possible to predict the stereoselectivity of B. sub lipase A towards ketoprofen vinyl Ester?.

  3. Research Letters

    1. Top of page
    2. Issue Information
    3. Research Articles
    4. Research Letters
    1. Structure-Based Design, Synthesis, and Antifungal Activity of New Triazole Derivatives (pages 309–313)

      Chunquan Sheng, Xiaoying Che, Wenya Wang, Shengzheng Wang, Yongbing Cao, Jianzhong Yao, Zhenyuan Miao and Wannian Zhang

      Article first published online: 20 JUN 2011 | DOI: 10.1111/j.1747-0285.2011.01138.x

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      A series of phenylacetamide-containing new azoles with good in vitro antifungal activity were rationally designed and synthesized.

    2. Exploring QSARs for 5-Lipoxygenase (5-LO) Inhibitory Activity of 2-Substituted 5-Hydroxyindole-3-Carboxylates by CoMFA and CoMSIA (pages 314–321)

      Junxia Zheng, Gaokeng Xiao, Jialiang Guo, Yang Zheng, Hao Gao, Suqing Zhao, Kun Zhang and Pinghua Sun

      Article first published online: 13 JUN 2011 | DOI: 10.1111/j.1747-0285.2011.01146.x

      Thumbnail image of graphical abstract

      The satisfactory CoMFA model predicted a q2 value of 0.779 and an r2 value of 0.957 and revealed that electrostatic and steric properties play a significant role in potency. The best CoMSIA model, based on a combination of steric, hydrophobic, and H-bond donor effects, predicted a q2 value of 0.816 and an r2 value of 0.953. The models were graphically interpreted using CoMFA and CoMSIA contour plots and the results provide a solid basis for future rational design of more active 5-LO inhibitors.

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