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Chemical Biology & Drug Design

Cover image for Vol. 79 Issue 4

April 2012

Volume 79, Issue 4

Pages i–iii, 369–615

  1. Issue Information

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

      Article first published online: 21 MAR 2012 | DOI: 10.1111/j.1747-0285.2011.01353.x

  2. Research Articles

    1. Top of page
    2. Issue Information
    3. Research Articles
    4. Research Letters
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      Computational Chemical Biology: Identification of Small Molecular Probes that Discriminate between Members of Target Protein Families (pages 369–375)

      Dilyana Dimova and Jürgen Bajorath

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01297.x

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      Shown are an exemplary active compound and its target selectivity profile. The number of targets the compound is active against and the profile score are reported.

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      Synthesis of Potent Dishevelled PDZ Domain Inhibitors Guided by Virtual Screening and NMR Studies (pages 376–383)

      Jufang Shan, Xinxin Zhang, Ju Bao, Robert Cassell and Jie J. Zheng

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01295.x

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      We expanded our in silico search to examine the chemical space near previously developed inhibitors and identified additional compounds as Dvl PDZ inhibitors; then based on a quantitative structure-activity relation analysis of these inhibitors and the structural studies of the PDZ domain in complex with the inhibitors, we designed and synthesized a group of new, further optimized compounds. Two rounds of synthesis and testing yielded six compounds that have greatly improved binding affinity to the Dvl PDZ domain.

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      Synthesis of Novel Nalidixic Acid-Based 1,3,4-Thiadiazole and 1,3,4-Oxadiazole Derivatives as Potent Antibacterial Agents (pages 384–397)

      Nisha Aggarwal, Rajesh Kumar, Prem Dureja and Jitender Mohan Khurana

      Article first published online: 1 FEB 2012 | DOI: 10.1111/j.1747-0285.2011.01316.x

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      Nalidixic acid based thia(oxa)diazole derivatives were synthesized and screened for their antibacterial activity. 3-{4-[(4-Chloro-phenylamino)-methyl]-5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl}-1-ethyl-7-methyl-1H-1,8-naphthyridin-4-one has emerged as the potent antibacterial compounds with MIC 6.25–125 μg/mL against five test micro organisms.

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      Understanding the Physical Interactions in the FGF21/FGFR/β-Klotho Complex: Structural Requirements and Implications in FGF21 Signaling (pages 398–410)

      Junming Yie, Wei Wang, Liying Deng, Lei-Ting Tam, Jennitte Stevens, Michelle M. Chen, Yang Li, Jing Xu, Richard Lindberg, Randy Hecht, Murielle Véniant, Ching Chen and Minghan Wang

      Article first published online: 1 FEB 2012 | DOI: 10.1111/j.1747-0285.2012.01325.x

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      (i) Deletion of the D1/linker region (the D1 and the D1-D2 linker) from FGFR1c led to β-Klotho-independent receptor activation by FGF21, and the D1/linker region of FGFR1c inhibited β-Klotho/FGFR1c interaction. (ii) Deletion of the D1/linker region enhanced the formation of the FGF21/β-Klotho/FGFR1c ternary complex in both Biacore and asymmetrical flow field flow fractionation studies. (iii) The N-terminus of FGF21 directly mediated FGFR1c activation, and the N-terminus of FGF21 is involved in the interaction with FGFR1c and FGF21/β-Klotho/FGFR1c ternary complex formation.

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      Insight into Selectivity of Peptidomimetic Inhibitors with Modified Statine Core for Plasmepsin II of Plasmodium falciparum over Human Cathepsin D (pages 411–430)

      Brice Dali, Melalie Keita, Eugene Megnassan, Vladimir Frecer and Stanislav Miertus

      Article first published online: 21 MAR 2012 | DOI: 10.1111/j.1747-0285.2011.01276.x

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      Intermolecular interactions of peptidomimetic inhibitors of plasmepsin II of Plasmodium faciparum containing a modified statine core has been modeled taking advantage of crystal structures of pfPlmII and human cathepsin D with bound inhibitors with the goal of gaining insight into structural requirements underlying the target selectivity.

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      A Novel Pharmacophore Model to Identify Leads for Simultaneous Inhibition of Anti-coagulation and Anti-inflammatory Activities of Snake Venom Phospholipase A2 (pages 431–441)

      Abdul Wadood, Syed Abid Ali, Rabia Sattar, Muhammad Arif Lodhi and Zaheer Ul-Haq

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01281.x

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      Pharmacophore models were generated based upon 32 structurally diverse lead hits were identified for simultaneous inhibition of anti-coagulant and anti-inflammatory affects of snake venom enzyme PLA2.

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      QSAR Study of 4-Aryl-4H-Chromenes as a New Series of Apoptosis Inducers Using Different Chemometric Tools (pages 442–458)

      Mehdi Khoshneviszadeh, Najmeh Edraki, Ramin Miri, Alireza Foroumadi and Bahram Hemmateenejad

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01284.x

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      The apoptosis inducing activity data of a series of 4-aryl-4H-chromenes based on three cell lines (T47D, H1299 and DLD-1) have been subjected to quantitative structure-activity relationship (QSAR) analysis. Models of high statistical qualities were obtained for each cell line using GA-PLS method. The results revealed that 2D-autocorrelation descriptors and dipole moments as a quantum chemical parameter are important structural parameters that significantly influence the activity in all three type cell lines.

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      Synthesis and Pharmacological Evaluation of Novel Arginine Analogs as Potential Inhibitors of Acetylcholine-Induced Relaxation in Rat Thoracic Aortic Rings (pages 459–469)

      Manish Jain, Manoj Kumar Barthwal, Wahajul Haq, Seturam B. Katti and Madhu Dikshit

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01286.x

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      Key findings: (i) Homoarginine methyl ester with free guanido group inhibits acetylcholine induced relaxation. (ii) Role of a proton on guanido group is crucial. (iii) Dipeptide derivative with dimethyl guanido group are better than respective monomers.

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      MCR Synthesis of Praziquantel Derivatives (pages 470–477)

      Haixia Liu, Samia William, Eberhardt Herdtweck, Sanaa Botros and Alexander Dömling

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01288.x

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      The two step sequence of Ugi and Pictet-Spengler reaction allows for the hitherto unprecedented short, convergent and fast synthesis of derivatives of the schistosomiasis drug praziquantel. More than 30 novel derivatives in each of the Ugi starting materials are described and tested. A few compounds show comparable activity to praziquantel in a worm viability assay.

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      Virtual Design of Chemical Penetration Enhancers for Transdermal Drug Delivery (pages 478–487)

      Sharath Golla, Brian J. Neely, Eric Whitebay, Sundar Madihally, Robert L. Robinson Jr and Khaled A. M. Gasem

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01293.x

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      A new genetic algorithm (GAs) and non-linear quantitative structure-property relationship (QSPR) models have been integrated to develop a reliable virtual screening algorithm for generation of potential chemical penetration enhancers. The GA-QSPR algorithm has been implemented successfully to identify potential CPEs for transdermal drug delivery of insulin. Validation of the newly-identified CPE molecular structures was conducted through carefully designed experiments, which elucidated the cytotoxicity and permeability of the CPEs.

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      Design and Synthesis of N-Substituted Indazole-3-Carboxamides as Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors (pages 488–496)

      Maulik R. Patel, Kashyap G. Pandya, Cesar A. Lau-Cam, Satyakam Singh, Maria A. Pino, Blase Billack, Kurt Degenhardt and Tanaji T. Talele

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01302.x

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      A new series of indazole-3-carboxamide derivatives as PARP-1 inhibitors have been identified. Most potent inhibitor was further evaluated in rats for its protective action against diabetes induced by a treatment with streptozotocin.

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      Evaluation of Antiproliferative Effect of N-(alkyladamantyl)phthalimides In vitro (pages 497–506)

      Margareta Horvat, Lidija Uzelac, Marko Marjanović, Nikola Cindro, Oliver Franković, Kata Mlinarić-Majerski, Marijeta Kralj and Nikola Basarić

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01305.x

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      A series of adamantylphthalimides 115 were synthesized. The compounds were tested for antiproliferative activity in vitro on a series of five human cancer lines: MCF-7 (breast carcinoma), SW 620 and HCT 116 (colon carcinoma), MOLT-4 (acute lymphoblastic leukemia), H 460 (lung carcinoma).

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      Transport Characteristics of Endomorphin-2 Analogues in Brain Capillary Endothelial Cells (pages 507–513)

      Jayapal Reddy Mallareddy, Géza Tóth, Csilla Fazakas, Judit Molnár, Péter Nagyőszi, Andrzej W. Lipkowski, István A. Krizbai and Imola Wilhelm

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01306.x

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      In this study we have analyzed the transport characteristics of EM-2 and three of its analogues (Dmt-Pro-Phe-Phe-NH2, Tyr-(1S,2R)Acpc-Phe-Phe-NH2 and Tyr-(1S,2R)Achc-Phe-Phe-NH2) using an in vitro BBB model. The permeability coefficient of the analogues was significantly higher than that of EM-2, suggesting increased BBB penetration properties. We conclude that due to their good peptidase resistance and improved transport through brain endothelial cells these EM-2 analogues may have better analgesic properties in vivo.

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      Quantum Chemical QSAR Models to Distinguish Between Inhibitory Activities of Sulfonamides Against Human Carbonic Anhydrases I and II and Bovine IV Isozymes (pages 514–522)

      Omar Deeb, Mohammad Goodarzi and Padmaker V. Khadikar

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01309.x

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      A QSAR analysis has been performed on three types of CA isozyme inhibitory activities for 53 sulfonamides using MLR, PC-ANN and CR-PCR analyses. It was observed that the interaction between the ligand and receptor varies from one type of CA isozyme to another. The results obtained show that linear and non-linear regression analyses are useful tools to distinguish between the inhibitory activities of sulfonamides toward different CA isozyme types: I, II and IV.

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      Synthesis and Antitumor Activity of Dehydroepiandrosterone Derivatives on Es-2, A549, and HepG2 Cells in vitro (pages 523–529)

      Xue-Kun Liu, Bai-Jun Ye, Yan Wu, Ji-Xing Nan, Zhen-Hua Lin and Hu-Ri Piao

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01311.x

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      A series of dehydroepiandrosterone derivatives containing an acid ester were synthesized and evaluated the antitumor activity on ES-2, A549 and HepG2 cells. Most compounds showed antitumor activity, especially compound 2i on ES-2 cells, 1c on A549 cells and 2o on HepG2 cells, respectively, and the IC50 value of compound 1c on A549 cells exhibited the single μm range.

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      Selective Flexibility of Side-Chain Residues Improves VEGFR-2 Docking Score using AutoDock Vina (pages 530–534)

      Rui M. V. Abreu, Hugo J. C. Froufe, Maria-João R. P. Queiroz and Isabel C. F. R. Ferreira

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01313.x

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      A docking study of selective side-chain residues flexibility was performed using VEGFR-2 tyrosine kinase as protein target and ADVina as docking software. The flexible Glu885 flexible conformation provided the best results, with a significant docking score improvement across all used VEGFR-2 crystal structures. The methodology presented may be a valuable tool for virtual screening projects using VEGFR-2 or applied to other therapeutic protein targets of interest.

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      Conformational Preferences of Proline Derivatives Incorporated into Vasopressin Analogues: NMR and Molecular Modelling Studies (pages 535–547)

      Emilia Sikorska, Dariusz Sobolewski and Anna Kwiatkowska

      Article first published online: 1 FEB 2012 | DOI: 10.1111/j.1747-0285.2012.01318.x

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      In this study, AVP analogues modified with proline derivatives were examined using NMR spectroscopy and molecular modelling methods. Bearing in mind the role of biological membrane in peptide hormone interactions with the target receptor, explorations of the conformational and dynamic properties of the ligands studied were carried out in a membrane-mimicking environment.

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      Synthesis and Hypolipidemic Activity of Novel 2-(4-(2-Amino-6-(4-Substituted Phenyl) Pyrimidin-4-yl)-2-Substituted Phenoxy) Acetic Acid Derivatives (pages 548–552)

      Santosh N. Mokale, Maheshwari T. Shete, Sameer I. Shaikh and Devanand B. Shinde

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2012.01319.x

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      A novel series of 2-(4-(2-amino-6-(4- substituted phenyl) pyrimidin-4-yl)-2-substituted phenoxy) acetic acid derivatives were efficiently synthesized. The synthesized compounds were evaluated for their in vivo hypolipidemic activity, using high fat diet induced hyperlipidemia. Some of these compounds showed significant anti-hyperlipidemic activity.

  3. Research Letters

    1. Top of page
    2. Issue Information
    3. Research Articles
    4. Research Letters
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      DFT-based QSAR Models to Predict the Antimycobacterial Activity of Chalcones (pages 553–559)

      Nilakshi Barua, Pubalee Sarmah, Iftikar Hussain, Ramesh C. Deka and Alak K. Buragohain

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01289.x

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      QSAR analysis on antimycobacterial activity of synthesized chalcone derivatives have been investigated using density functional theory (DFT) based descriptors. Effect of solvents on QSAR equations has also been studied.

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      3D-QSAR and Molecular Docking Studies on 3-Anilino-4-Arylmaleimide Derivatives as Glycogen Synthase Kinase-3β Inhibitors (pages 560–571)

      Mymoona Akhtar and Prasad V. Bharatam

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01291.x

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      By identifying some key features from CoMSIA and CoMFA contour maps somenew anilino aryl maleimide derivatives have been designed. The designed molecules showed better binding affinity in terms of estimated docking scores with respect to the already reported ones.

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      A Modeling Study for Structure Features of β-N-acetyl-D-hexosaminidase from Ostrinia furnacalis and its Novel Inhibitor Allosamidin: Species Selectivity and Multi-Target Characteristics (pages 572–582)

      Yanli Wang, Tian Liu, Qing Yang, Zhong Li and Xuhong Qian

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01301.x

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      Structure model of OfHex1 shows differences to HsHex but shares common features to chitinase, and shares a common inhibitor: allosamidin.

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      Computational Design of Peptide Inhibitor Based on Modifications of Proregion from Plutella xylostella Midgut Trypsin (pages 583–593)

      Jitrayut Jitonnom, Khemika Lomthaisong and Vannajan S. Lee

      Article first published online: 30 JAN 2012 | DOI: 10.1111/j.1747-0285.2011.01312.x

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      A series of peptides (AAAPGHR, AAAPGRR, AAAPGKR, AAPGHRI, APGHRIV, PGHRIVG, AAAAPGH and AAAAAPG) was in silico designed based on histidine-mutated and frame-shifted modifications of the proregion (AAAPGHR) of Plutella xylostella midgut trypsin. Among the eight peptides, AAAPGRR was found to give the best docking scores, showing a strong binding to its cognate enzyme. Further, the obtained structure of trypsin-AAAPGRR complex was found to share a similar binding mode with a crystal structure of plant protease-inhibitor complex.

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      1-Benzyl-1,2,3,4-Tetrahydro-β-Carboline as Channel Blocker of N-Methyl-d-Aspartate Receptors (pages 594–599)

      Marlene Espinoza-Moraga, Julio Caballero, Friedemann Gaube, Thomas Winckler and Leonardo S. Santos

      Article first published online: 1 FEB 2012 | DOI: 10.1111/j.1747-0285.2012.01317.x

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      1-Benzyl-1,2,3,4-tetrahydro-β-carboline establishes the main interactions inside the vestibule region of NMDA receptor described previously for the high-affinity NMDA receptor blocker, MK-801.

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      In Silico Characterization of Atypical Kinase PFD0975w from Plasmodium Kinome: A Suitable Target For Drug Discovery (pages 600–609)

      Vishal Trivedi and Swagata Nag

      Article first published online: 1 FEB 2012 | DOI: 10.1111/j.1747-0285.2012.01321.x

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      Molecular model of PfRIO-2 has subtle but significant difference from HuRIO-2 to exploit for drug development. This is the first structural reports to identify peptide binding regions on RIO-2 kinase. Our results are first attempt to characterize and validate atypical protein kinase, PFD0975w as drug target to develop drug against malaria.

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      Antiplasmodial activity of steroidal chalcones: evaluation of their effect on hemozoin synthesis and the new permeation pathway of Plasmodium falciparum-infected erythrocyte membrane (pages 610–615)

      Brijesh S. Sisodia, Arvind S. Negi, Mahendra P. Darokar, Upendra N. Dwivedi and Suman P. S. Khanuja

      Article first published online: 1 FEB 2012 | DOI: 10.1111/j.1747-0285.2012.01323.x

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      Chalcone derivatives on estradiol framework were evaluated for their ability to inhibit the growth and developement of the malaria parasite Plasmodium falciparum. Two of the derivatives (1 and 10) exhibited moderate antiplasmodial activity with good selectivity ratio against vero cells. Active derivatives did not affect hemozoin synthesis of the parasite but inhibited parasite-induced new permeation pathway in erythrocyte membrane measured by sorbitol-induced hemolysis.

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