Chemical Biology & Drug Design

Cover image for Vol. 85 Issue 2

February 2015

Volume 85, Issue 2

Pages i–iii, 99–243

  1. Issue Information

    1. Top of page
    2. Issue Information
    3. Editor's Choice
    4. Research Articles
    1. Issue Information (pages i–iii)

      Article first published online: 14 JAN 2015 | DOI: 10.1111/cbdd.12404

  2. Editor's Choice

    1. Top of page
    2. Issue Information
    3. Editor's Choice
    4. Research Articles
    1. Computer-Aided Drug Discovery Approach Finds Calcium Sensitizer of Cardiac Troponin (pages 99–106)

      Steffen Lindert, Monica X. Li, Brian D. Sykes and J. Andrew McCammon

      Article first published online: 11 JUL 2014 | DOI: 10.1111/cbdd.12381

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      In the fight against heart failure, therapeutics that increase the calcium sensitivity of the thin filament are a promising option to improve heart contractile power. Here, we combined computational drug discovery methods and solution NMR titration assays to identify a novel calcium sensitizer which binds to cTnC and the cTnC-cTnI147–163 complex. Its presence increases the affinity of switch peptide to cTnC by approximately a factor of two, making its action comparable to that of known levosimendan analogues.

  3. Research Articles

    1. Top of page
    2. Issue Information
    3. Editor's Choice
    4. Research Articles
    1. Comparative Analysis of Various Electrostatic Potentials on Docking Precision Against Cyclin-Dependent Kinase 2 Protein: A Multiple Docking Approach (pages 107–118)

      Sunil K. Tripathi, Rajendran Naga Soundarya, Poonam Singh and Sanjeev K. Singh

      Article first published online: 12 JUL 2014 | DOI: 10.1111/cbdd.12376

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      Different semiempirical (RM1, AM1, PM3, MNDO) and ab intio (HF, DFT) charge models were investigated for their performance in prediction of docking pose against CDK2 proteins. The preliminary results point out that AM1 charge model can provide precious insight into the design of new potent and selective CDK2 inhibitors with enhanced success rate.

    2. Hologram Quantitative Structure Activity Relationship, Docking, and Molecular Dynamics Studies of Inhibitors for CXCR4 (pages 119–136)

      Chongqian Zhang, Chunmiao Du, Zhiwei Feng, Jingyu Zhu and Youyong Li

      Article first published online: 10 JUL 2014 | DOI: 10.1111/cbdd.12377

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      We perform HQSAR, docking, and molecular dynamics studies of inhibitors for CXCR4. We obtain a reliable HQSAR model (q2 = 0.779) and we perform docking and MD study of CXCR4 with inhibitor bound. We find that the binding are affected by two crucial residues Asp97 and Glu288 of CXCR4. And the butyl amine moiety of AMD11070 is critical for its high antiretroviral activity.

    3. Drug Repurposing Based on Drug–Drug Interaction (pages 137–144)

      Bin Zhou, Rong Wang, Ping Wu and De-Xin Kong

      Article first published online: 2 JUL 2014 | DOI: 10.1111/cbdd.12378

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      The associations between drugs were established based on drug-drug interaction data and rendered with a drug association network. In the network, drugs with similar anatomical therapeutic chemical (ATC) codes (indicating they have similar functions) gathered together. And it was also demonstrated that this network can be well applied to the prediction of targets for drugs and is complementary to other target prediction methods.

    4. Hybrid Molecule from Farnesylthiosalicylic Acid-diamine and Phenylpropenoic Acid as Ras-related Signaling Inhibitor with Potent Antitumor Activities (pages 145–152)

      Yong Ling, Zhiqiang Wang, Xuemin Wang, Xianghua Li, Xinyang Wang, Wei Zhang, Hong Dai, Li Chen and Yihua Zhang

      Article first published online: 8 SEP 2014 | DOI: 10.1111/cbdd.12393

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      Novel series of Farnesylthiosalicylic acid-diamine/phenylpropenoic acid hybrids were synthesized and biologically evaluated. Compound 12f, with the strongest anti-proliferative activity, exerted selectively grow inhibitory activity against tumor cells but not non-tumor liver cell proliferation, and inhibited both Ras related signaling and phosphorylated NF-κB synergetically which may be advantageous to its strong antitumor activities in vitro.

    5. Positional Isomerization of A Non-Cleavable Combi-Molecule Dramatically Altered Tumor Cell Response Profile (pages 153–162)

      Ying Huang, Zakaria Rachid, Lisa Peyrard, Zhor Senhaji Mouhri, Christopher Williams and Bertrand J. Jean-Claude

      Article first published online: 24 SEP 2014 | DOI: 10.1111/cbdd.12402

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      A quinazoline-based inhibitor of EGFR containing a chloroethylamino group at the 6-position exhibited strong DNA-damaging properties, irreversible EGFR inhibition, and apoptosis. Shifting the group to the 7-position led to a significant decrease in DNA-damaging potential and 10-fold weaker EGFR inhibition.

    6. Highly Potential Antiplasmodial Restricted Peptides (pages 163–171)

      Torres Marcelo Der Torossian, Adriana F. Silva, Flávio L. Alves, Margareth L. Capurro, Antonio Miranda and Oliveira Vani Xavier Jr.

      Article first published online: 11 JUL 2014 | DOI: 10.1111/cbdd.12354

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      Five angiotensin II-restricted analogs that contain disulfide bridges were synthesized to analyze their effect on antiplasmodial activity. The results indicate that two of the analogs had higher antiplasmodium activity (92% and 98% activity) than angiotensin II (88% activity), measured by fluorescence microscopy. The results obtained with the new restricted analogs showed that the insertion position to preserve the hydrophobic interactions among the non-polar residues is important to the antiplasmodial activity.

    7. Design, Synthesis and Evaluation of Rhodanine Derivatives as Aldose Reductase Inhibitors (pages 172–180)

      Yogesh P. Agrawal, Mona Y. Agrawal and Arun K. Gupta

      Article first published online: 11 JUL 2014 | DOI: 10.1111/cbdd.12369

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      Series of substituted 5-phenylbenzoate rhodanine analogs were synthesized and evaluated for their ALR inhibitory activity. The docking study of synthesized compounds was carried out, which revealed that the 5-phenylbenzoate moiety deeply influenced the key π-π stacking while 4-oxo-2-thioxothiazolidines contributed in hydrogen bond interactions.

    8. Discovery of Novel 17-Phenylethylaminegeldanamycin Derivatives as Potent Hsp90 Inhibitors (pages 181–188)

      Zhenyu Li, Lejiao Jia, Jifeng Wang, Xingkang Wu, Guowei Shi, Chunhua Lu and Yuemao Shen

      Article first published online: 26 JUN 2014 | DOI: 10.1111/cbdd.12371

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      Compound 2y was revealed to be a promising antitumor agent through the synthesis, structure-activity relationship analysis and hepatotoxicity evaluation of 26 novel 17-phenylethylaminegeldanamycin derivatives, which showed the most potent antitumor activity against LNCap cells and the least hepatotoxicity. The binding model of compound 2y to Hsp90 was simulated by Amber12 and shown by PyMoL.

    9. Structural Basis for Low-Affinity Binding of Non-R2 Carboxylate-Substituted Tricyclic Quinoline Analogs to CK2α: Comparative Molecular Dynamics Simulation Studies (pages 189–200)

      Yue Zhou, Xitao Li, Na Zhang and Rugang Zhong

      Article first published online: 26 JUN 2014 | DOI: 10.1111/cbdd.12372

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      A combination of molecular modeling techniques are applied to gain insight into the structural mechanisms through which the non-R2 carboxylate substituent influence CX-4945 analogs binding affinity. An allosteric pathway between the deviated ligands and the affected regions (G-loop, C-loop and β4/β5 loop) was proposed.

    10. Targeting Dormant Tuberculosis Bacilli: Results for Molecules with a Novel Pyrimidone Scaffold (pages 201–207)

      Rohit R. Joshi, Avinash Barchha, Vijay M. Khedkar, Raghuvir R. S. Pissurlenkar, Sampa Sarkar, Dhiman Sarkar, Rohini R. Joshi, Ramesh A. Joshi, Anamik K. Shah and Evans C. Coutinho

      Article first published online: 12 JUL 2014 | DOI: 10.1111/cbdd.12373

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      This paper reports the second molecule after TMC-207, with the ability to inhibit tuberculosis bacilli in its dormant phase. The paper reports molecules with a novel Pyrimidone Scaffold, the synthesis of which was accomplished with a modified multi-component Biginelli reaction. A classification model was generated using recursive partitioning (RP) technique to identify structural characteristics of the molecules with their varying activities.

    11. The Potential Roles of Cell Surface pHs in Bioactive Peptide Activation (pages 208–215)

      Long Chen and Jun F. Liang

      Article first published online: 7 JUL 2014 | DOI: 10.1111/cbdd.12374

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      Cells from different tissues and organs have distinguished cell surface pHs. Cell surface pH could greatly affect the interactions of pH sensitive peptides with cells and contributed signifcantly to the biological activity of peptides. A peptide designed based on the surface pH difference between normal and cancer cells showed selective toxicity to cancer cells.

    12. Synthesis and Evaluation of a New Series of 3,5-bis((5-bromo-6-methyl-2-t-aminopyrimidin-4-yl)thio)-4H-1,2,4-triazol-4-amines and their Cyclized Products ‘Pyrimidinylthio Pyrimidotriazolothiadiazines’ as 15- Lipo-Oxygenase Inhibitors (pages 216–224)

      Tayebe Asghari, Mehdi Bakavoli, Mohammad Rahimizadeh, Hossein Eshghi, Sattar Saberi, Azam Karimian, Farzin Hadizadeh and Moreteza Ghandadi

      Article first published online: 10 JUL 2014 | DOI: 10.1111/cbdd.12375

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      A series of new 3,5-bis(substituted pyrimidinylthio)triazolamines 4ag and their cyclized products ‘pyrimidinylthio pyrimidotriazolothiadiazines’ 5ag were designed, synthesized, and evaluated as potential inhibitors of 15-lipoxygenase (15-LO). The compounds 4ag were also evaluated by docking with 15-lipo-oxygenase enzyme. Compounds 4d (NR2 = 1-methylpiperazine) and 4f (NR2 = 1-ethylpiperazine) showed the best IC50 of 15-LO inhibition (IC50 = 9 and 12 µm, respectively).

    13. 2-(Hetero(aryl)methylene)hydrazine-1-carbothioamides as Potent Urease Inhibitors (pages 225–230)

      Aamer Saeed, Aqeel Imran, Pervaiz A. Channar, Mohammad Shahid, Wajahat Mahmood and Jamshed Iqbal

      Article first published online: 10 JUL 2014 | DOI: 10.1111/cbdd.12379

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      2-(Hetero(aryl)methylene)hydrazine-1- carbothioamides 3-thiazolocoumarinyl derivatives were synthesized and evaluated for anti-urease activity, most of the assayed compounds were potent inhibitors of the enzyme, and their binding modes were studied by molecular docking experiments.

    14. Discovery, Optimization, and Pharmacophore Modeling of Oleanolic Acid and Analogues as Breast Cancer Cell Migration and Invasion Inhibitors Through Targeting Brk/Paxillin/Rac1 Axis (pages 231–243)

      Heba E. Elsayed, Mohamed R. Akl, Hassan Y. Ebrahim, Asmaa A. Sallam, Eman G. Haggag, Amel M. Kamal and Khalid A. El Sayed

      Article first published online: 15 JUL 2014 | DOI: 10.1111/cbdd.12380

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      Bioassay-guided fractionation of Terminali bentzoe L. leaves extract identified the triterpene oleanolic acid as its major breast cancer cell migration inhibitor. Further chemical modifications afforded more potent semisynthetic analogues. Western blot analysis indicated the anticancer activities to be related to the suppression of Brk/Paxillin/Rac1 axis. Pharmacophore modeling was conducted to better understand structural binding epitopes important for the antimigratory activity.