Cover image for Vol. 11 Issue 3

Early View (Online Version of Record published before inclusion in an issue)

Editor-in-Chief: Natalia Ortúzar

Impact Factor: 2.968

ISI Journal Citation Reports © Ranking: 2014: 19/59 (Chemistry Medicinal); 83/255 (Pharmacology & Pharmacy)

Online ISSN: 1860-7187

Associated Title(s): Angewandte Chemie International Edition, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemBioChem, Medicinal Research Reviews, Molecular Informatics


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  1. Full Papers

    1. Fragment Screening of Soluble Epoxide Hydrolase for Lead Generation—Structure-Based Hit Evaluation and Chemistry Exploration

      Dr. Yafeng Xue, Dr. Thomas Olsson, Dr. Carina A Johansson, Dr. Linda Öster, Dr. Hans-Georg Beisel, Dr. Mattias Rohman, Dr. David Karis and Dr. Stefan Bäckström

      Article first published online: 4 FEB 2016 | DOI: 10.1002/cmdc.201500575

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      The screening room: Both fragment screening and high-throughput screening are used in an integrated hit-finding and lead-generation strategy. Two distinct scaffolds are identified as tractable starting points for further chemistry work. Significant induced-fit binding is observed for the 2-phenylbenzimidazole-4-sulfonamide compounds. A new lead series may be generated if features from the two series are combined together.

  2. Communications

    1. Structural Re-engineering of the α-Helix Mimetic JY-1-106 into Small Molecules: Disruption of the Mcl-1–Bak-BH3 Protein–Protein Interaction with 2,6-Di-Substituted Nicotinates

      Brandon Drennen, Jacob A. Scheenstra, Dr. Jeremy L. Yap, Lijia Chen, Maryanna E. Lanning, Dr. Braden M. Roth, Dr. Paul T. Wilder and Dr. Steven Fletcher

      Article first published online: 4 FEB 2016 | DOI: 10.1002/cmdc.201500461

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      2,6-Di-substituted nicotinates inhibit the myeloid cell leukemia-1 (Mcl-1) oncoprotein with potencies in the single-digit micromolar range, as determined by a fluorescence polarization competition assay. Direct binding to Mcl-1 was confirmed by 2D 1H–15N HSQC NMR spectroscopy. Inspired by a fragment of a previously reported α-helix mimetic, the small-molecules reported herein are more druglike and, owing to greater synthetic accessibility, future optimization is expected to be elementary.

  3. Minireviews

    1. Substrate Activity Screening (SAS) and Related Approaches in Medicinal Chemistry

      Rafaela Gladysz, Prof. Dr. Anne-Marie Lambeir, Dr. Jurgen Joossens, Prof. Dr. Koen Augustyns and Prof. Dr. Pieter Van der Veken

      Article first published online: 4 FEB 2016 | DOI: 10.1002/cmdc.201500569

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      Building on building blocks: SAS is a straightforward fragment-based method with great potential for the design of enzyme inhibitors. A number of aspects require special attention in order to maximize the efficiency of this approach. These include proper design of the substrate library and screening assay, determination of adequate kinetic and thermodynamic substrate parameters, and selection of an appropriate warhead or isostere.

  4. Reviews

    1. Cancer Immunotherapy: Selected Targets and Small-Molecule Modulators

      Prof. Dr. Hilmar Weinmann

      Article first published online: 2 FEB 2016 | DOI: 10.1002/cmdc.201500566

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      Small molecules for immuno-oncology: Cancer immunotherapy is currently generating a lot of excitement in the scientific community, as well as new hope for many cancer patients given some recent clinical successes. The discovery and development of new small-molecule modulators is a rapidly growing research area for medicinal chemists in immuno-oncology. This review provides a brief introduction into recent trends related to some selected targets and pathways for cancer immunotherapy and their small-molecule pharmacological modulators.

  5. Book Reviews

    1. New Horizons in Predictive Drug Metabolism and Pharmacokinetics. Edited by Alan G. E. Wilson

      Prof. Johannes Kirchmair

      Article first published online: 2 FEB 2016 | DOI: 10.1002/cmdc.201600013

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      RSC, Cambridge 2015. 422 pp., hardcover, £175.00.—ISBN 978-1-84973-828-6

  6. Full Papers

    1. Fragment-Based Protein–Protein Interaction Antagonists of a Viral Dimeric Protease

      Dr. Jonathan E. Gable, Dr. Gregory M. Lee, Dr. Timothy M. Acker, Kaitlin R. Hulce, Eric R. Gonzalez, Dr. Patrick Schweigler, Dr. Samu Melkko, Dr. Christopher J. Farady and Prof. Charles S. Craik

      Article first published online: 28 JAN 2016 | DOI: 10.1002/cmdc.201500526

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      Dimer disruption: Using a fragment-based screen (FBS), we identified several structurally unrelated compounds that inhibit protein–protein interactions of a dimeric human herpesvirus protease. NMR spectroscopy verifies that these fragments bind at or near a hot-spot residue located on the dimer interface. SAR by catalogue discovered analogues with enhanced potency over the primary hits.

  7. Communications

    1. Phage Selection of Peptide Macrocycles against β-Catenin To Interfere with Wnt Signaling

      Davide Bertoldo, Dr. Maola M. G. Khan, Pierre Dessen, Prof. Werner Held, Prof. Joerg Huelsken and Prof. Christian Heinis

      Article first published online: 26 JAN 2016 | DOI: 10.1002/cmdc.201500557

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      Hit the target within a target: Bicyclic peptides that bind to different surface regions of β-catenin were developed by phage display. Several of the ligands compete with the binding of ICAT and therefore bind to the prime target site on β-catenin for therapeutic intervention.

    2. Antivirulence Isoquinolone Mannosides: Optimization of the Biaryl Aglycone for FimH Lectin Binding Affinity and Efficacy in the Treatment of Chronic UTI

      Cassie Jarvis, Dr. Zhenfu Han, Vasilios Kalas, Roger Klein, Jerome S. Pinkner, Dr. Bradley Ford, Jana Binkley, Dr. Corinne K. Cusumano, Dr. Zachary Cusumano, Dr. Laurel Mydock-McGrane, Prof. Scott J. Hultgren and Prof. James W. Janetka

      Article first published online: 26 JAN 2016 | DOI: 10.1002/cmdc.201600006

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      Biofilm blockers: Cyclizing the aglycone amide nitrogen of biphenyl mannosides 5 and 7 onto the B-ring generates fused heterocyclic biaryl mannoside 22 with enhanced potency as determined by a bacteria-mediated hemagglutination assay. N-Substitution of 22 on the isoquinolone produced a unique subseries of mannose-based FimH antagonists with improved activity. We discovered pyridyl-substituted mannoside 25 b, which prevents biofilm formation by uropathogenic E. coli with unprecedented potency.

  8. Full Papers

    1. Different Binding Modes of Small and Large Binders of GAT1

      Dr. Thomas Wein, Dr. Marilena Petrera, Dr. Lars Allmendinger, Dr. Georg Höfner, Dr. Jörg Pabel and Prof. Dr. Klaus T. Wanner

      Article first published online: 25 JAN 2016 | DOI: 10.1002/cmdc.201500534

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      What a difference a pose makes! N-Substitution of (R)-nipecotic acid with a residue as in tiagabine increases the pKi from 4.5 to 7.4 at the GABA transporter, GAT1. The same N-substituent on (R)-proline changes the pKi from 0.3 to 6.4! Our data suggest a change in GAT1 binding pose induced by N-substitution. Thus, the N-butyl derivatives provide a better estimate for binding potencies than the respective pure acids.

    2. Synthesis and Biological Assessment of Racemic Benzochromenopyrimidinimines as Antioxidant, Cholinesterase, and Aβ1−42 Aggregation Inhibitors for Alzheimer's Disease Therapy

      Youssef Dgachi, Dr. Lhassane Ismaili, Damijan Knez, Dr. Mohamed Benchekroun, Dr. Hélène Martin, Dr. Natalia Szałaj, Sarah Wehle, Dr. Oscar M. Bautista-Aguilera, Vincent Luzet, Alexandre Bonnet, Prof. Barbara Malawska, Prof. Stanislav Gobec, Dr. Mourad Chioua, Prof. Dr. Michael Decker, Prof. Fakher Chabchoub and Prof. José Marco-Contelles

      Article first published online: 25 JAN 2016 | DOI: 10.1002/cmdc.201500539

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      Inhibitors for AD: Novel benzochromenopyrimidinimines as antioxidants and inhibitors of cholinesterase and β-amyloid (Aβ1−42) aggregation are described. We identified one compound in particular as a new multitarget-directed ligand: it is a potent antioxidant and human acetylcholinesterase and Aβ1−42 aggregation inhibitor with potential application in the treatment of Alzheimer's disease (AD).

  9. Communications

    1. Screening, Synthesis, and In Vitro Evaluation of Vinyl Sulfones as Inhibitors of Complement-Dependent Cytotoxicity in Neuromyelitis Optica

      Eun Ji Ju, Seul Ki Yeon, Dr. Jong-Hyun Park, Dr. So Young Cheon, Ji Won Choi, Dr. Taehwan Ha, Bo Ko Jang, Siwon Kim, Yong Gu Kang, Dr. Hayoung Hwang, Dr. Sung Jin Cho, Prof. Eunji Cheong, Prof. Yong Sun Bahn, Dr. Ae Nim Pae, Prof. Sung Min Kim and Dr. Ki Duk Park

      Article first published online: 25 JAN 2016 | DOI: 10.1002/cmdc.201500546

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      NMO in sight: A target-based small-molecule screening method was used to identify compounds that block the binding of neuromyelitis optica (NMO)-specific immunoglobulin G autoantibodies (NMO-IgG) to aquaporin-4 (AQP4). Vinyl sulfone compound 5 c (shown) exhibited potent inhibition of NMO-IgG/complement-dependent cytotoxicity in both AQP4 overexpressing U87-MG cells and primary astrocytes by blocking the binding of NMO-IgG to AQP4.

  10. Full Papers

    1. Hitting a Moving Target: How Does an N-Methyl Group Impact Biological Activity?

      Yen Chin Koay, Nicole L. Richardson, Samantha S. Zaiter, Jessica Kho, Sheena Y. Nguyen, Daniel H. Tran, Ka Wai Lee, Laura K. Buckton and Prof. Shelli R. McAlpine

      Article first published online: 25 JAN 2016 | DOI: 10.1002/cmdc.201500572

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      Seven cyclic peptides were synthesized and tested for biological activity. These new macrocycles were designed to understand how moving an N-methyl group around the peptide backbone impacts activity. The lead non-methylated structure was found to inhibit heat-shock protein 90 (Hsp90), which prompted us to test two of the most potent analogues for their Hsp90-inhibitory activity. Our data show that the N-methyl group controls the conformation of the macrocycle, which has a dramatic impact on cytotoxicity and binding affinity.

  11. Communications

    1. Application of Site-Specific Spin Labeling for NMR Detecting Inhibitor-Induced Conformational Change of HIV-1 Reverse Transcriptase

      Supaporn Seetaha, Dr. Maho Yagi-Utsumi, Dr. Takumi Yamaguchi, Dr. Kentaro Ishii, Prof. Supa Hannongbua, Prof. Kiattawee Choowongkomon and Prof. Koichi Kato

      Article first published online: 25 JAN 2016 | DOI: 10.1002/cmdc.201500554

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      Paramagnetism-assisted NMR techniques were successfully applied to detect inhibitor-induced conformational changes of a drug target using HIV-1 reverse transcriptase as a model protein. Observation of conformation-dependent paramagnetic relaxation enhancements with site-specific spin labeling offers a new strategy to identify allosteric inhibitors using protein-based drug screening methods.

  12. Full Papers

    1. Structure-Guided Discovery of Antitubercular Agents That Target the Gyrase ATPase Domain

      Dr. Variam U. Jeankumar, Dr. Shalini Saxena, Dr. Rahul Vats, Rudraraju Srilakshmi Reshma, Renuka Janupally, Dr. Pushkar Kulkarni, Prof. Perumal Yogeeswari and Prof. Dharmarajan Sriram

      Article first published online: 25 JAN 2016 | DOI: 10.1002/cmdc.201500556

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      Debilitating Mtb gyrase ATPase: We present an intriguing class of small-molecule inhibitors of the gyrase ATPase domain that have promising in vitro potency against replicative and dormant strains of Mycobacterium tuberculosis H37Rv. The results of preliminary toxicity and PK evaluations are encouraging, as the lead candidate shows promising characteristics for rational drug design and development against M. tuberculosis ATPase.

    2. Bioavailability Studies and in vitro Profiling of the Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor UCPH-102

      Dr. Isabell Haym, Dr. Tri H. V. Huynh, Dr. Stinne W. Hansen, Dr. Martin H. F. Pedersen, Dr. Josep A. Ruiz, Dr. Mette N. Erichsen, Dr. Mikko Gynther, Walden E. Bjørn-Yoshimoto, Dr. Bjarke Abrahamsen, Dr. Jesper F. Bastlund, Dr. Christoffer Bundgaard, Anette L. Eriksen, Prof. Anders A. Jensen and Prof. Lennart Bunch

      Article first published online: 21 JAN 2016 | DOI: 10.1002/cmdc.201500527

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      EAAT1 inhibition beyond the BBB: In the present study, oral administration (40 mg kg−1) of the selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor UCPH-102 in rats yielded respective plasma and brain concentrations of 10.5 and 6.67 μm after 1 h. In vitro profiling of UCPH-102 (10 μm) at 51 central nervous system targets in radioligand binding assays strongly suggests that the compound is fully selective for EAAT1.

  13. Communications

    1. A Potent and Selective P-gp Modulator for Altering Multidrug Resistance Due to Pump Overexpression

      Dr. Stefano Guglielmo, Dr. Marialessandra Contino, Prof. Loretta Lazzarato, Dr. Maria Grazia Perrone, Dr. Marco Blangetti, Prof. Roberta Fruttero and Prof. Nicola Antonio Colabufo

      Article first published online: 21 JAN 2016 | DOI: 10.1002/cmdc.201500538

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      Simple chemical modification of MC70, a well-known but rather nonselective P-glycoprotein (P-gp) inhibitor, led to a very potent and selective P-gp ligand (EC50=5.2 nm). The derivative displayed an intriguing double-faced mechanism of action, acting as both substrate and modulator. The synthesis of MC70 was also greatly improved, using a straightforward and protecting-group-free Suzuki–Miyaura coupling of halophenol.

  14. Full Papers

    1. Structure–Activity Studies of Bis-O-Arylglycolamides: Inhibitors of the Integrated Stress Response

      Dr. Brian R. Hearn, Priyadarshini Jaishankar, Dr. Carmela Sidrauski, Jordan C. Tsai, Dr. Punitha Vedantham, Dr. Shaun D. Fontaine, Prof. Peter Walter and Prof. Adam R. Renslo

      Article first published online: 20 JAN 2016 | DOI: 10.1002/cmdc.201500483

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      Stress management: Herein we describe structure–activity studies of bis-O-arylglycolamides, first-in-class Integrated Stress Response InhiBitors (ISRIB). ISRIB analogues make cells insensitive to the effects of eIF2α phosphorylation by activating eIF2B, the guanine exchange factor for eIF2. ISRIB analogues are thought to bind and stabilize a protein–protein interface in the dimeric form of the eIF2B heteropentameric protein complex.

  15. Minireviews

    1. Broadly Neutralizing Antibody-Guided Carbohydrate-Based HIV Vaccine Design: Challenges and Opportunities

      Chang-Cheng Liu, Dr. Xiu-Jing Zheng and Prof. Xin-Shan Ye

      Article first published online: 13 JAN 2016 | DOI: 10.1002/cmdc.201500498

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      Anti-HIV glycoconjugates: Broadly neutralizing antibodies provide conserved glycan epitopes of HIV, which can guide the design of vaccines. Many carbohydrate-based vaccines have been designed, but none have succeeded in practice thus far. Herein we review new strategies toward the design of high-affinity antigens and immunization regimens that have been proposed and tested.

  16. Full Papers

    1. New Insight into the Structure–Activity Relationships of the Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors UCPH-101 and UCPH-102

      Dr. Stinne W. Hansen, Dr. Mette N. Erichsen, Dr. Tri H. V. Huynh, Dr. Josep A. Ruiz, Dr. Isabell Haym, Dr. Walden E. Bjørn-Yoshimoto, Dr. Bjarke Abrahamsen, Jeanette Hansen, Dr. Morten Storgaard, Anette L. Eriksen, Prof. Anders A. Jensen and Prof. Lennart Bunch

      Article first published online: 12 JAN 2016 | DOI: 10.1002/cmdc.201500525

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      Inhibition of glutamate uptake: 63 new analogues of the selective EAAT1 inhibitor UCPH-101 were synthesized and characterized pharmacologically. Analogues that unexpectedly displayed inhibitory activities at EAAT1 were identified. Furthermore, separation of the four stereoisomers of analogue 14 g revealed that, in agreement with a study of a related scaffold, the R configuration at C4 is mandatory for inhibitory activity, whereas both C7 diastereomers are active as EAAT1 inhibitors.

    2. Very Important Paper

      Identification and Optimization of Anthranilic Acid Based Inhibitors of Replication Protein A

      Dr. James D. Patrone, Nicholas F. Pelz, Brittney S. Bates, Prof. Elaine M. Souza-Fagundes, Bhavatarini Vangamudi, Demarco V. Camper, Dr. Alexey G. Kuznetsov, Carrie F. Browning, Dr. Michael D. Feldkamp, Dr. Andreas O. Frank, Benjamin A. Gilston, Prof. Edward T. Olejniczak, Prof. Olivia W. Rossanese, Prof. Alex G. Waterson, Prof. Walter J. Chazin and Prof. Stephen W. Fesik

      Article first published online: 8 JAN 2016 | DOI: 10.1002/cmdc.201500479

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      Blocking recruitment: A high-throughput screening campaign and subsequent structure-guided optimization led to the identification of anthranilic acid based molecules that occupy the entire basic cleft of the 70 kDa subunit of replication protein A (RPA70N) and bind the protein with sub-micromolar affinity.

  17. Minireviews

    1. Progress in the Development of non-BET Bromodomain Chemical Probes

      Natalie H. Theodoulou, Prof. Nicholas C. O. Tomkinson, Dr. Rab K. Prinjha and Dr. Philip G. Humphreys

      Article first published online: 8 JAN 2016 | DOI: 10.1002/cmdc.201500540

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      All BETs are off: The development of chemical probes for non-BET bromodomains is a new and rapidly advancing field. Chemical probes for these bromodomains will help to elucidate their biological roles and potentially lead to the development of new medicines. This review summarises the progress made towards this goal and highlights areas for future work.

  18. Full Papers

    1. Virtual Screening and Experimental Validation Identify Novel Inhibitors of the Plasmodium falciparum Atg8–Atg3 Protein–Protein Interaction

      Dr. Adelaide U. P. Hain, Alexia S. Miller, Dr. Jelena Levitskaya and Dr. Jürgen Bosch

      Article first published online: 8 JAN 2016 | DOI: 10.1002/cmdc.201500515

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      Autophagy is essential to Plasmodium falciparum, which causes malaria. We virtually targeted a protein interaction in this pathway which is distinct from the human system. A small-molecule inhibitor from this screen shows modest inhibitory activity in parasite cultures, demonstrating the possibility of selectively inhibiting Plasmodium autophagy.

    2. ω-Imidazolyl- and ω-Tetrazolylalkylcarbamates as Inhibitors of Fatty Acid Amide Hydrolase: Biological Activity and in vitro Metabolic Stability

      Dr. Tobias Terwege, Walburga Hanekamp, David Garzinsky, Prof. Dr. Simone König, Dr. Oliver Koch and Prof. Dr. Matthias Lehr

      Article first published online: 6 JAN 2016 | DOI: 10.1002/cmdc.201500445

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      FAAH and away! Fatty acid amide hydrolase (FAAH) has emerged as an attractive target for the development of analgesic and anti-inflammatory drugs. Herein we describe the inhibition data of a series of carbamate inhibitors of this enzyme and investigations on the metabolic stability of these compounds in rat liver homogenate and porcine plasma. The esterases responsible for pronounced cleavage of some of these carbamates in plasma are also examined.

  19. Minireviews

    1. You have full text access to this OnlineOpen article
      Small-Molecule and Peptide Inhibitors of the Pro-Survival Protein Mcl-1

      Dr. Andrew M. Beekman and Dr. Lesley A. Howell

      Article first published online: 23 DEC 2015 | DOI: 10.1002/cmdc.201500497

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      The­ anti­ to pro-survival: The Bcl-2 family of proteins undergo a series of protein–protein interactions that regulate apoptosis. The pro-survival members of the Bcl-2 family, including Bcl-2 and Mcl-1, are commonly overexpressed in a number of cancers. The efficient modulation of Mcl-1 is still not represented in the clinic, despite its role in treatment resistance. This review covers the progress to date in modulating the activity of Mcl-1, by both stapled peptides and small molecules.

  20. Full Papers

    1. Development of Highly Potent GAT1 Inhibitors: Synthesis of Nipecotic Acid Derivatives by Suzuki–Miyaura Cross-Coupling Reactions

      Dr. Marilena Petrera, Dr. Thomas Wein, Dr. Lars Allmendinger, Dr. Miriam Sindelar, Dr. Jörg Pabel, Dr. Georg Höfner and Prof. Klaus T. Wanner

      Article first published online: 18 DEC 2015 | DOI: 10.1002/cmdc.201500490

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      Exploring the gap: Guided by molecular modeling studies, a series of nipecotic acid derivatives with different 2-biphenyl moieties on an N-butenyl linker were synthesized as potential GAT1 inhibitors. A 2′,4′-dichlorobiphenyl-2-yl derivative was found to be highly potent in binding and uptake assays and to display high subtype selectivity for GAT1.

  21. Reviews

    1. How To Design a Successful p53–MDM2/X Interaction Inhibitor: A Thorough Overview Based on Crystal Structures

      Natalia Estrada-Ortiz, Dr. Constantinos G. Neochoritis and Prof. Alexander Dömling

      Article first published online: 16 DEC 2015 | DOI: 10.1002/cmdc.201500487

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      Structures of interference: Plenty of novel small molecules with promising activity have been published as MDM2/X inhibitors. Research efforts over the past decade have led to several compounds that are currently in clinical trials for the treatment of various types of cancer. In this review, we discuss different categories of MDM2/X inhibitors with a special focus on crystal structures and binding modes.

  22. Communications

    1. Development and Application of a Virtual Screening Protocol for the Identification of Multitarget Fragments

      Dr. Giovanni Bottegoni, Dr. Marina Veronesi, Dr. Paola Bisignano, Dr. Puneet Kacker, Dr. Angelo D. Favia and Prof. Andrea Cavalli

      Article first published online: 10 DEC 2015 | DOI: 10.1002/cmdc.201500521

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      Multitasking for memory: Classical virtual ligand screening protocols can be efficiently adapted to work with fragments within the framework of polypharmacology. Herein we report the in silico discovery of a dual inhibitor of β-secretase 1 and glycogen synthase kinase 3β, highlighting a new and promising approach in the treatment of Alzheimer′s disease.

  23. Full Papers

    1. EPR Studies of V-ATPase with Spin-Labeled Inhibitors DCC and Archazolid: Interaction Dynamics with Proton Translocating Subunit c

      Jan Philipp Gölz, Dr. Svenja Bockelmann, Dr. Kerstin Mayer, Prof. Dr. Heinz-Jürgen Steinhoff, Prof. Dr. Helmut Wieczorek, Dr. Markus Huss, Dr. Johann P. Klare and Prof. Dr. Dirk Menche

      Article first published online: 10 DEC 2015 | DOI: 10.1002/cmdc.201500500

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      Near and DEER: Electron paramagnetic resonance (EPR) and double electron–electron resonance (DEER) studies of V-ATPase in complex with spin-labeled inhibitors DCC and archazolid have enabled insight into the noncovalent binding dynamics and analysis of the enzyme′s key functional subunit c. These studies also demonstrate the general utility of natural product derived spin labels as innovative tools for chemical biology.

  24. Minireviews

    1. STAT3-Interacting Proteins as Modulators of Transcription Factor Function: Implications to Targeted Cancer Therapy

      Dr. Jennifer E. Yeh and Dr. David A. Frank

      Article first published online: 10 DEC 2015 | DOI: 10.1002/cmdc.201500482

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      STAT3 turns the key: The transcription factor STAT3 regulates critical cellular processes such as proliferation, survival, and self-renewal. While it is tightly regulated under normal conditions, inappropriate activation of STAT3 is a common driver of the malignant behavior of cancer cells. Increasing evidence suggests that the interaction between STAT3 and other proteins is a key modulator of its function, and altering these associations may be an important therapeutic strategy for cancer treatment.

  25. Full Papers

    1. Small-Molecule Stabilization of the 14-3-3/Gab2 Protein–Protein Interaction (PPI) Interface

      David Bier, Dr. Maria Bartel, Katharina Sies, Sebastian Halbach, Dr. Yusuke Higuchi, Dr. Yu Haranosono, Dr. Tilman Brummer, Prof. Nobuo Kato and Dr. Christian Ottmann

      Article first published online: 8 DEC 2015 | DOI: 10.1002/cmdc.201500484

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      A stabilizing influence: We have identified a semi-synthetic, natural product protein–protein interaction (PPI) stabilizer that enhances the binding of the adapter protein 14-3-3 to oncogenic Gab2. Stabilization of this PPI is expected to attenuate the pro-oncogenic activity of Gab2. Our molecule, ISIR-005, represents chemical proof-of-principle for the druggability of the 14-3-3/Gab2 interface.

  26. Reviews

    1. You have full text access to this OnlineOpen article
      Fighting Cancer with Transition Metal Complexes: From Naked DNA to Protein and Chromatin Targeting Strategies

      Dr. Giulia Palermo, Dr. Alessandra Magistrato, Dr. Tina Riedel, Thibaud von Erlach, Prof. Curt A. Davey, Prof. Paul J. Dyson and Prof. Ursula Rothlisberger

      Article first published online: 4 DEC 2015 | DOI: 10.1002/cmdc.201500478

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      Metal mechanisms: Transition metal anticancer agents can exert their action by binding to different biological targets, including double-stranded DNA, proteins, and protein/DNA complexes packed in chromatin. Herein we review some relevant studies—based on platinum and ruthenium compounds—showing how the interplay between experimental and computational data has played a key role in clarifying the selectivity for protein versus DNA, thus elucidating relevant drug mechanistic features at the molecular level.

  27. Communications

    1. Very Important Paper

      Pyrimidine Triazole Thioether Derivatives as Toll-Like Receptor 5 (TLR5)/Flagellin Complex Inhibitors

      Lei Yan, Jiaqi Liang, Chengbo Yao, Peiyao Wu, Xianfeng Zeng, Dr. Kui Cheng and Prof. Dr. Hang Yin

      Article first published online: 4 DEC 2015 | DOI: 10.1002/cmdc.201500471

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      Through high-throughput screening, we have successfully developed a series of small-molecule probes as novel inhibitors of flagellin binding to TLR5. TH1020 (pictured) was identified as a potent antagonist of TLR5 signaling with promising activity (IC50=0.85±0.12 μM) and specificity. TH1020 was shown to repress the expression of downstream TNF-α signaling pathways mediated by the TLR5/flagellin complex. Based on molecular docking simulation, TH1020 was suggested to compete with flagellin and disrupt its association with TLR5.

  28. Minireviews

    1. Inhibitors of Ras–SOS Interactions

      Dr. Shaoyong Lu, Dr. Hyunbum Jang, Prof. Jian Zhang and Prof. Ruth Nussinov

      Article first published online: 2 DEC 2015 | DOI: 10.1002/cmdc.201500481

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      Undruggable­ Rascals! Ras oncoproteins are ‘undruggable’ due to the lack of any evident suitable pockets on Ras surfaces where a molecule might bind tightly. Ras activation is regulated by GEFs, such as SOS, which form protein–protein interactions (PPIs) with Ras, the rate-limiting step in Ras activation. Herein we focus on data involved in the design of small-molecule modulators or peptide mimetics that target the interface of the Ras–SOS PPI, which has gained increasing recognition for treating Ras mutant cancers.

  29. Communications

    1. You have full text access to this OnlineOpen article
      Identification of Small-Molecule Inhibitors of the Antiapoptotic Protein Myeloid Cell Leukaemia-1 (Mcl-1)

      Dr. Andrew M. Beekman, Dr. Maria A. O'Connell and Dr. Lesley A. Howell

      Article first published online: 30 NOV 2015 | DOI: 10.1002/cmdc.201500488

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      Breaking up the party: Overexpression of the antiapoptosis Bcl-2 protein family members is commonly observed in cancers, with myeloid cell leukemia-1 (Mcl-1) often being responsible for resistance to radio and chemotherapy. Exploiting the Mcl-1 selective apoptosis regulating protein Noxa, novel small molecules capable of modulating Mcl-1 are identified and evaluated.

  30. Full Papers

    1. Serpin A1 C-Terminal Peptides as Collagen Turnover Modulators

      Simona Pascarella, Dr. Caterina Tiberi, Dr. Giuseppina Sabatino, Dr. Francesca Nuti, Prof. Anna Maria Papini, Prof. Lisa Giovannelli and Prof. Paolo Rovero

      Article first published online: 30 NOV 2015 | DOI: 10.1002/cmdc.201500472

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      Time to heal: A) Synthesis of overlapping peptides of serpin A1 C-terminal portion: SA1-I, SA1-II, SA1-III. B) Biological screening on cultured normal human dermal fibroblasts: dose–response curve for peptide SA1-III. Our data highlight that this decapeptide is a promising lead compound for further development in the search for wound-healing agents to be included in future pharmaceutical formulas.

    2. High-Throughput Screening (HTS) by NMR Guided Identification of Novel Agents Targeting the Protein Docking Domain of YopH

      Dr. Angel Bottini, Dr. Bainan Wu, Dr. Elisa Barile, Dr. Surya K. De, Dr. Marilisa Leone and Prof. Dr. Maurizio Pellecchia

      Article first published online: 23 NOV 2015 | DOI: 10.1002/cmdc.201500441

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      HTS by NMR: High-throughput screening (HTS) by NMR is used to identify novel agents that can disrupt the protein–protein interactions between the Yersinia toxin YopH-NT and its cellular substrates. A novel agent was identified of the sequence Ac-F-pY-cPG-D-P-NH2 (pY=phosphotyrosine; cPG=cyclopentyl glycine) with a Kd value against YopH-NT of 310 nM. The data reported further demonstrate the utility of the “HTS by NMR” approach in deriving novel peptide mimetics targeting protein–protein interactions.

  31. Communications

    1. You have full text access to this OnlineOpen article
      The Molecular Basis for Dual Fatty Acid Amide Hydrolase (FAAH)/Cyclooxygenase (COX) Inhibition

      Dr. Giulia Palermo, Dr. Angelo D. Favia, Dr. Marino Convertino and Dr. Marco De Vivo

      Article first published online: 23 NOV 2015 | DOI: 10.1002/cmdc.201500507

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      A duel with pain! The molecular basis is investigated by molecular modeling and molecular dynamics simulations for the dual inhibition of fatty acid amide hydrolase (FAAH) and the cyclooxygenase enzymes (COXs) by ARN2508 (2-[3-fluoro-4-[3-(hexylcarbamoyloxy)phenyl]phenyl]propanoic acid), a multitarget-directed ligand that combines, in a single scaffold, the pharmacophoric elements often needed to block FAAH and COX. The results offer new insights for the rational design of anti-inflammatory agents.

  32. Minireviews

    1. You have full text access to this OnlineOpen article
      Cyclic and Macrocyclic Peptides as Chemical Tools To Recognise Protein Surfaces and Probe Protein–Protein Interactions

      Teresa A. F. Cardote and Dr. Alessio Ciulli

      Article first published online: 13 NOV 2015 | DOI: 10.1002/cmdc.201500450

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      Can peptides do the job? Peptides can structurally mimic features of protein interfaces, and this makes them attractive candidates to probe and explore sites of protein–protein interactions (PPIs). Improving their stability and physicochemical properties has been the main challenge. This review focuses on cyclic and macrocyclic peptides that aim to address these limitations and how they have been successfully used to target PPIs.

  33. Full Papers

    1. You have full text access to this OnlineOpen article
      Combined Use of Oligopeptides, Fragment Libraries, and Natural Compounds: A Comprehensive Approach To Sample the Druggability of Vascular Endothelial Growth Factor

      Dr. Núria Bayó-Puxan, Dr. Ricard Rodríguez-Mias, Dr. Michael Goldflam, Dr. Martin Kotev, Sonia Ciudad, Dr. Christopher J. Hipolito, Dr. Monica Varese, Prof. Hiroaki Suga, Dr. Ramón Campos-Olivas, Dr. Xavier Barril, Prof. Víctor Guallar, Dr. Meritxell Teixidó, Dr. Jesús García and Prof. Ernest Giralt

      Article first published online: 10 NOV 2015 | DOI: 10.1002/cmdc.201500467

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      Master of its domain: Vascular endothelial growth factor (VEGF) is considered a relevant target for anticancer therapy with low druggability. We describe an extensive study exploring oligopeptides, fragment-based libraries, and natural products to target the receptor binding site of VEGF. The successful ligands have the capacity to expose hydrophobic groups that interact with the hydrophobic hot spots at the interacting VEGF surface patch.

    2. Aminobenzimidazoles and Structural Isomers as Templates for Dual-Acting Butyrylcholinesterase Inhibitors and hCB2R Ligands To Combat Neurodegenerative Disorders

      Dominik Dolles, Martin Nimczick, Matthias Scheiner, Jacqueline Ramler, Patricia Stadtmüller, Edgar Sawatzky, Antonios Drakopoulos, Prof. Dr. Christoph Sotriffer, Dr. Hans-Joachim Wittmann, Dr. Andrea Strasser and Prof. Dr. Michael Decker

      Article first published online: 9 NOV 2015 | DOI: 10.1002/cmdc.201500418

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      Two in one: In this study dual-acting compounds were identified and optimized, and binding modes were computationally investigated to yield ligands that can bind selectively to the cannabinoid receptor 2 (CB2R) and inhibit butyrylcholinesterase (BChE) in the same concentration range. Such compounds serve as leads for multitarget drugs acting at both GPCRs and enzymes for therapeutic application in neurodegenerative disorders.

    3. Light-Tunable Generation of Singlet Oxygen and Nitric Oxide with a Bichromophoric Molecular Hybrid: a Bimodal Approach to Killing Cancer Cells

      Dr. Aurore Fraix, Dr. Marco Blangetti, Dr. Stefano Guglielmo, Dr. Loretta Lazzarato, Dr. Nino Marino, Dr. Venera Cardile, Dr. Adriana C. E. Graziano, Dr. Ilse Manet, Prof. Roberta Fruttero, Prof. Alberto Gasco and Prof. Salvatore Sortino

      Article first published online: 5 NOV 2015 | DOI: 10.1002/cmdc.201500396

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      Two-pronged zapping: A bichromophoric molecular hybrid was synthesized by combining a tailored BODIPY derivative as singlet oxygen (1O2) photosensitizer with a nitroaniline derivative as nitric oxide (NO) photodonor. These two chromogenic units absorb in distinct regions of the visible spectrum, and thus photogeneration of the cytotoxic 1O2 and NO species can be regulated by appropriately tuning the excitation light. This bimodal action amplifies the photomortality of melanoma cancer cells.

    4. Multitarget Strategy to Address Alzheimer’s Disease: Design, Synthesis, Biological Evaluation, and Computational Studies of Coumarin-Based Derivatives

      Dr. Serena Montanari, Prof. Manuela Bartolini, Dr. Paolo Neviani, Dr. Federica Belluti, Prof. Silvia Gobbi, Dr. Letizia Pruccoli, Prof. Andrea Tarozzi, Dr. Federico Falchi, Prof. Vincenza Andrisano, Dr. Przemysław Miszta, Prof. Andrea Cavalli, Prof. Sławomir Filipek, Prof. Alessandra Bisi and Dr. Angela Rampa

      Article first published online: 28 OCT 2015 | DOI: 10.1002/cmdc.201500392

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      Forget me not: Coumarin derivatives related to AP2238 are reported as disease-modifying multitarget-directed ligands for the treatment of Alzheimer’s disease. Coumarin-based derivatives were designed and synthesized with the aim to expand the biological profile of AP2238. One compound emerged as a nanomolar inhibitor of human acetylcholinesterase with significant potency at blocking Aβ42 self-aggregation, and endowed with additional promising neuroprotective behavior.

    5. Nature-Inspired Multifunctional Ligands: Focusing on Amyloid-Based Molecular Mechanisms of Alzheimer’s Disease

      Dr. Elena Simoni, Melania M. Serafini, Prof. Dr. Manuela Bartolini, Roberta Caporaso, Antonella Pinto, Dr. Daniela Necchi, Dr. Jessica Fiori, Prof. Dr. Vincenza Andrisano, Prof. Dr. Anna Minarini, Dr. Cristina Lanni and Prof. Dr. Michela Rosini

      Article first published online: 26 OCT 2015 | DOI: 10.1002/cmdc.201500422

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      Shedding light on Aβ: Nature-inspired ligands 13 allow exploration of the molecular mechanisms potentially engaged in chronic β-amyloid (Aβ) injuries. This study supports the involvement of oxidative stress in Aβ function, and p53 was found to emerge as a potential mediator of their functional interplay.

  34. Concepts

    1. Metabolism-Activated Multitargeting (MAMUT): An Innovative Multitargeting Approach to Drug Design and Development

      Prof. Péter Mátyus and Prof. Christina L. L. Chai

      Article first published online: 26 OCT 2015 | DOI: 10.1002/cmdc.201500406

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      Chasing the MAMUT! We describe the concept of metabolism-activated multitargeting (MAMUT), which is based on the combination of synergistic effects of a parent drug and its active metabolite(s). Our own example and some representatives of successful drugs indicate that this concept may represent a valuable drug design strategy.

  35. Full Papers

    1. Potent and Selective Inhibitors of Trypanosoma cruzi Triosephosphate Isomerase with Concomitant Inhibition of Cruzipain: Inhibition of Parasite Growth through Multitarget Activity

      Elena Aguilera, Javier Varela, Estefanía Birriel, Elva Serna, Susana Torres, Gloria Yaluff, Dr. Ninfa Vera de Bilbao, Beatriz Aguirre-López, Nallely Cabrera, Selma Díaz Mazariegos, Dr. Marieta Tuena de Gómez-Puyou, Dr. Armando Gómez-Puyou, Dr. Ruy Pérez-Montfort, Lucia Minini, Dr. Alicia Merlino, Dr. Hugo Cerecetto, Dr. Mercedes González and Dr. Guzmán Alvarez

      Article first published online: 23 OCT 2015 | DOI: 10.1002/cmdc.201500385

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      Two birds. One stone. Multitarget agents were developed that act against triosephosphate isomerase (TIM) and cruzipain, two key enzymes in Trypanosoma cruzi, the causative agent of Chagas disease. The compounds exhibited nanomolar range inhibition of TcTIM and protection profiles in vivo, with the best compound exhibiting an IC50 value of 86 nM against TcTIM in an enzymatic assay, and an IC50 value of 600 nM against the epimastigote form of T. cruzi, Tulahuen 2 strain.

  36. Minireviews

    1. A Double Whammy: Targeting Both Fatty Acid Amide Hydrolase (FAAH) and Cyclooxygenase (COX) To Treat Pain and Inflammation

      Dr. Rita Scarpelli, Dr. Oscar Sasso and Prof. Daniele Piomelli

      Article first published online: 21 OCT 2015 | DOI: 10.1002/cmdc.201500395

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      Accumulated evidence suggests that drugs that target both fatty acid amide hydrolase (FAAH) and cyclooxygenase (COX) should have substantial analgesic and anti-inflammatory efficacy combined with decreased gastrointestinal toxicity. Herein we review the basic rationale of multitarget FAAH/COX inhibition and the state of the art of medicinal chemistry efforts in this area.

  37. Communications

    1. Design, Synthesis and in vitro Evaluation of Indolotacrine Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease

      Ondrej Benek, Dr. Ondrej Soukup, Marketa Pasdiorova, Lukas Hroch, Dr. Vendula Sepsova, Petr Jost, Martina Hrabinova, Dr. Daniel Jun, Prof. Kamil Kuca, Dominykas Zala, Dr. Rona R. Ramsay, Prof. José Marco-Contelles and Dr. Kamil Musilek

      Article first published online: 2 OCT 2015 | DOI: 10.1002/cmdc.201500383

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      MAO meets ChE! By using a multitarget-directed ligand approach, a series of novel compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The most promising compound, indolotacrine 9 b, was found to be a potent inhibitor of both cholinesterases and MAO A and a moderately potent inhibitor of MAO B.

  38. Minireviews

    1. Concepts and Molecular Aspects in the Polypharmacology of PARP-1 Inhibitors

      Dr. Daniela Passeri, Prof. Emidio Camaioni, Dr. Paride Liscio, Dr. Paola Sabbatini, Dr. Martina Ferri, Dr. Andrea Carotti, Dr. Nicola Giacchè, Prof. Roberto Pellicciari, Prof. Antimo Gioiello and Prof. Antonio Macchiarulo

      Article first published online: 1 OCT 2015 | DOI: 10.1002/cmdc.201500391

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      Right on PAR: The increased understanding of molecular aspects in the polypharmacology of PARP-1 inhibitors is driving the development of these compounds toward novel cancer therapies. It provides an explanation for the varied sensitivity or resistance of cancer cells toward certain compounds, and clues as to why some drug candidates work better than others in clinical settings. Herein we provide an overview of the distinct levels of the polypharmacology of PARP-1 inhibitors, including inter-family, intra-family, and multi-signaling polypharmacology.

  39. Full Papers

    1. Systematic Assessment of Molecular Selectivity at the Level of Targets, Bioactive Compounds, and Structural Analogues

      Dr. Ye Hu and Prof. Dr. Jürgen Bajorath

      Article first published online: 11 SEP 2015 | DOI: 10.1002/cmdc.201500340

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      Selectivity cliffs: The issues of target selectivity and compound promiscuity are important for medicinal chemistry. Here, these two characteristics are evaluated in silico using alternative “cliff” concepts. Shown is an exemplary selectivity cliff formed by analogues with inverse selectivity, i.e., one compound is selective for target A over B (A/B, blue background) and the other for B over A (B/A, red).

    2. Predicting Molecular Targets for Small-Molecule Drugs with a Ligand-Based Interaction Fingerprint Approach

      Dr. Ran Cao and Dr. Yanli Wang

      Article first published online: 17 JUL 2015 | DOI: 10.1002/cmdc.201500228

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      Off-target prediction: Herein we introduce a ligand-based interaction fingerprint (LIFt) approach to predict molecular targets for small-molecule drugs. The power of this approach is evident for both retrospectively modeling the polypharmacology of established kinase inhibitors and prospectively predicting new targets for clinical drug candidates.


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