RSC Medicinal Chemistry Blog

The articles below are some of the most read MedChemComm articles in April, May and June 2017.

Review Articles:

Multivalent glycoconjugates as vaccines and potential drug candidates
Sumati Bhatia, Mathias Dimde and Rainer Haag
DOI: 10.1039/C4MD00143E

Surface plasmon resonance for the characterization of bacterial polysaccharide antigens: a review
Barbara Brogioni and Francesco Berti
DOI: 10.1039/C4MD00088A

Recent advances in the rational design and optimization of antibacterial agents
Jesse A. Jones, Kristopher G. Virga, Giuseppe Gumina and Kirk E. Hevener
DOI: 10.1039/C6MD00232C

Polypharmacology modelling using proteochemometrics (PCM): recent methodological developments, applications to target families, and future prospects
Isidro Cortés-Ciriano, Qurrat Ul Ain, Vigneshwari Subramanian, Eelke B. Lenselink, Oscar Méndez-Lucio, Adriaan P. IJzerman, Gerd Wohlfahrt, Peteris Prusis, Thérèse E. Malliavin, Gerard J. P. van Westen and Andreas Bender
DOI: 10.1039/C4MD00216D

Protein–ligand (un)binding kinetics as a new paradigm for drug discovery at the crossroad between experiments and modelling
M. Bernetti, A. Cavalli and L. Mollica
DOI: 10.1039/C6MD00581K

Structural biology and chemistry of protein arginine methyltransferases
Matthieu Schapira and Renato Ferreira de Freitas
DOI: 10.1039/C4MD00269E

Small molecule-mediated protein knockdown as a new approach to drug discovery
Christopher P. Tinworth, Hannah Lithgow and Ian Churcher
DOI: 10.1039/C6MD00347H

Chemical probes and inhibitors of bromodomains outside the BET family
Moses Moustakim, Peter G. K. Clark, Duncan A. Hay, Darren J. Dixon and Paul E. Brennan
DOI: 10.1039/C6MD00373G

Amphiphilic designer nano-carriers for controlled release: from drug delivery to diagnostics
Malinda Salim, Hiroyuki Minamikawa, Akihiko Sugimura and Rauzah Hashim
DOI: 10.1039/C4MD00085D

2-[¹⁸F]Fluoroethyl tosylate – a versatile tool for building ¹⁸F-based radiotracers for positron emission tomography
Torsten Kniess, Markus Laube, Peter Brust and Jörg Steinbach
DOI: 10.1039/C5MD00303B

Structural features of many circular and leaderless bacteriocins are similar to those in saposins and saposin-like peptides
K. M. Towle and J. C. Vederas
DOI: 10.1039/C6MD00607H

Bacterial lipid membranes as promising targets to fight antimicrobial resistance, molecular foundations and illustration through the renewal of aminoglycoside antibiotics and emergence of amphiphilic aminoglycosides
Marie-Paule Mingeot-Leclercq and Jean-Luc Décout
DOI: 10.1039/C5MD00503E

Research Articles:

Towards understanding cell penetration by stapled peptides
Qian Chu, Raymond E. Moellering, Gerard J. Hilinski, Young-Woo Kim, Tom N. Grossmann, Johannes T.-H. Yeh and Gregory L. Verdine
DOI: 10.1039/C4MD00131A

Design and synthesis of DNA-encoded libraries based on a benzodiazepine and a pyrazolopyrimidine scaffold
M. Klika Škopić, O. Bugain, K. Jung, S. Onstein, S. Brandherm, T. Kalliokoski and A. Brunschweiger
DOI: 10.1039/C6MD00243A

Methods of protein surface PEGylation under structure preservation for the emulsion-based formation of stable nanoparticles
Lydia Radi, Matthias Fach, Mirko Montigny, Elena Berger-Nicoletti, Wolfgang Tremel and Peter R. Wich
DOI: 10.1039/C5MD00475F

Identification of imidazo[1,2-b]pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling
R. Moslin, D. Gardner, J. Santella, Y. Zhang, J. V. Duncia, C. Liu, J. Lin, J. S. Tokarski, J. Strnad, D. Pedicord, J. Chen, Y. Blat, A. Zupa-Fernandez, L. Cheng, H. Sun, C. Chaudhry, C. Huang, C. D’Arienzo, J. S. Sack, J. K. Muckelbauer, C. Chang, J. Tredup, D. Xie, N. Aranibar, J. R. Burke, P. H. Carter and D. S. Weinstein
DOI: 10.1039/C6MD00560H

Exploring the links between peptoid antibacterial activity and toxicity
H. L. Bolt, G. A. Eggimann, C. A. B. Jahoda, R. N. Zuckermann, G. J. Sharples and S. L. Cobb
DOI: 10.1039/C6MD00648E

Nonomuraea sp. ATCC 55076 harbours the largest actinomycete chromosome to date and the kistamicin biosynthetic gene cluster
Behnam Nazari, Clarissa C. Forneris, Marcus I. Gibson, Kyuho Moon, Kelsey R. Schramma and Mohammad R. Seyedsayamdost
DOI: 10.1039/C6MD00637J

Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H₄ receptor
Enade P. Istyastono, Albert J. Kooistra, Henry F. Vischer, Martien Kuijer, Luc Roumen, Saskia Nijmeijer, Rogier A. Smits, Iwan J. P. de Esch, Rob Leurs and Chris de Graaf
DOI: 10.1039/C5MD00022J

Human lysosomal acid lipase inhibitor lalistat impairs Mycobacterium tuberculosis growth by targeting bacterial hydrolases
J. Lehmann, J. Vomacka, K. Esser, M. Nodwell, K. Kolbe, P. Rämer, U. Protzer, N. Reiling and S. A. Sieber
DOI: 10.1039/C6MD00231E

Design and synthesis of potent and selective inhibitors of BRD7 and BRD9 bromodomains
Duncan A. Hay, Catherine M. Rogers, Oleg Fedorov, Cynthia Tallant, Sarah Martin, Octovia P. Monteiro, Susanne Müller, Stefan Knapp, Christopher J. Schofield and Paul E. Brennan
DOI: 10.1039/C5MD00152H

A fundamental view of enthalpy–entropy compensation
Ulf Ryde
DOI: 10.1039/C4MD00057A

Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor
Katherine S. England, Anthony Tumber, Tobias Krojer, Giuseppe Scozzafava, Stanley S. Ng, Michelle Daniel, Aleksandra Szykowska, KaHing Che, Frank von Delft, Nicola A. Burgess-Brown, Akane Kawamura, Christopher J. Schofield and Paul E. Brennan
DOI: 10.1039/C4MD00291A

From linked open data to molecular interaction: studying selectivity trends for ligands of the human serotonin and dopamine transporter
Barbara Zdrazil, Eva Hellsberg, Michael Viereck and Gerhard F. Ecker
DOI: 10.1039/C6MD00207B

Keep up-to-date with the latest issues of MedChemComm with our E-alerts

New, effective and selective COX-2 inhibitors that prevent inflammation have been reported in MedChemComm, in a new HOT article.

Cyclo-oxygenases are enzymes responsible for production of key inflammation-promoting molecules. Most drugs that target COX are non-selective and inhibit both COX-2, present in inflamed tissues, and COX-1, which has important regulatory functions in normal tissues. This can lead to gastro-intestinal side-effects such as ulcers.

Dr Marwa El-Gazzar’s group at the National Centre for Radiation Research and Technology in Cairo synthesized new derivatives of celecoxib, a recently discovered COX-2 selective inhibitor. They tested their effect on COX-2 in vitro to study their structure-activity relationship. Several of the compounds – many of which had sulfonamide moieties – were as effective as celecoxib at inhibiting COX-2, while having no effect on COX-1. These compounds were also the most effective at reducing paw oedema in rat models of inflammation, and had significant analgesic effects – importantly, they were non-toxic and did not cause ulceration.

The designed 1,3,4-thiadiazole derivatives and their proposed orientation into the selectivity site of COX-2.

The group also performed a molecular docking study to gain insight into the compounds’ inhibition mechanism. The compounds were found to strongly bind to the COX-2 active site, making them more effective. They could also enter a small pocket found only in COX-2 to bind to specific residues there – this gave them their selectivity.

The promising results for the reported compounds, as well as the mechanistic insights gained, could prove invaluable in developing new, selective drugs that can successfully treat inflammation without adverse side effects.


Read the full article here:

Synthesis of novel thiadiazole derivatives as selective COX-2 inhibitors
Fatma A. Ragab, Helmi I. Heiba, Marwa G. El-Gazzar,* Sahar M. Abou-Seri, Walaa A. El-Sabbagh and Reham M. El-Hazek
Med. Chem. Commun., 2016, Advance Article
DOI:  10.1039/C6MD00367B

Susannah May is a guest web writer for the RSC Journal blogs. She currently works in the Publishing Department of the Royal Society of Chemistry, and has a keen interest in biology and biomedicine, and the frontiers of their intersection with chemistry. She can be found on Twitter using @SusannahCIMay.

A new way of screening for small molecules using PNA-encoded libraries has been reported in MedChemComm. The technique, by Nicolas Winssinger’s group at the University of Geneva, identifies molecules that bind covalently to specific proteins. It could help to find new potent drugs in future.

DNA or PNA-encoded libraries are becoming a popular technique to easily screen large numbers of small molecules. However, it is often difficult to distinguish covalently binding molecules from those that bind non-covalently but with high affinity. Researchers are especially interested in covalent inhibitors as they permanently deactivate proteins and can make powerful drugs, with examples including aspirin and omeprazole.

Winssinger’s group synthesised two libraries of small molecules that were tagged with PNA “barcodes” and immobilised on a surface to form microarrays. These were incubated with a kinase solution and then washed. The group used a washing procedure which removed kinase bound with high-affinity non-covalent bonds, but left any kinase that was covalently bound to molecules. The DNA-PNA bonds were undamaged by the washing, and allowed easy identification and discrimination of the covalently bound and non-covalently bound molecules.

The method could be combined with other techniques such as next-generation sequencing in future. It promises to be the next step in efficient and rapid drug discovery.


Read the full article here:

Screening for covalent inhibitors using DNA display of small molecule libraries functionalized with cysteine reactive moieties
C. Zambaldo, J.-P. Daguer, J. Saarbach, S. Barluenga and N. Winssinger
Med. Chem. Commun. 2016, 7, 1340-1351

Part of the DNA Encoded Libraries themed collection in MedChemComm.

Susannah May is a guest web writer for the RSC Journal blogs. She currently works in the Publishing Department of the Royal Society of Chemistry, and has a keen interest in biology and biomedicine, and the frontiers of their intersection with chemistry. She can be found on Twitter using @SusannahCIMay.

The following MedChemComm articles have all been recommened by the reviewers of the articles as being particularly interesting or particularly significant research. These have all been made free to access until 12th December 2014. The order they appear in the list holds no special meaning or ranking.

Imidazole derivatives show anticancer potential by inducing apoptosis and cellular senescence
Gangavaram V. M. Sharma, Adepu Ramesh, Ashita Singh, Gourishetty Srikanth, Vankudoth Jayaram, Divya Duscharla, Jung Ho Jun, Ramesh Ummanni and Sanjay V. Malhotra  
DOI: 10.1039/C4MD00277F, Concise Article

Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor
Katherine S. England, Anthony Tumber, Tobias Krojer, Giuseppe Scozzafava, Stanley S. Ng, Michelle Daniel, Aleksandra Szykowska, KaHing Che, Frank von Delft, Nicola A. Burgess-Brown, Akane Kawamura, Christopher J. Schofield and Paul E. Brennan  
DOI: 10.1039/C4MD00291A, Concise Article
From themed collection Epigenetics

Computationally motivated synthesis and enzyme kinetic evaluation of N-(β-D-glucopyranosyl)-1,2,4-triazolecarboxamides as glycogen phosphorylase inhibitors
Jaida Begum, Gergely Varga, Tibor Docsa, Pál Gergely, Joseph M. Hayes, László Juhász and László Somsák  
DOI: 10.1039/C4MD00335G, Concise Article

Synthesis and biological evaluation of a series of aryl triazoles as firefly luciferase inhibitors
Haixiu Bai, Peng Zhu, Wenxiao Wu, Jing Li, Zhao Ma, Wei Zhang, Yanna Cheng, Lupei Du and Minyong Li  
DOI: 10.1039/C4MD00368C, Concise Article

Rational design of protein–protein interaction inhibitors
Didier Rognan  
DOI: 10.1039/C4MD00328D, Review Article

The following are HOT articles, as recommened by the reviewers of the articles. These have all been made free to access until 24th October:

Structure-based approaches towards identification of fragments for the low-druggability ATAD2 bromodomain
Apirat Chaikuad, Andrew M. Petros, Oleg Fedorov, Jing Xu and Stefan Knapp
Med. Chem. Commun., DOI: 10.1039/C4MD00237G, Concise Article
From themed collection Epigenetics

Gold compounds as aquaporin inhibitors: new opportunities for therapy and imaging
Andreia de Almeida, Graça Soveral and Angela Casini
Med. Chem. Commun., DOI: 10.1039/C4MD00265B, Review Article

A novel surface-coated nanocarrier for efficient encapsulation and delivery of camptothecin to cells
Rie Wakabayashi, Ryutaro Ishiyama, Noriho Kamiya and Masahiro Goto
Med. Chem. Commun., DOI: 10.1039/C4MD00179F, Concise Article
From themed collection In celebration of Seiji Shinkai’s 70^th Birthday

Peptide HIV fusion inhibitors: modifications and conjugations
Wei Liu, Jianjun Tan, Mohammadreza Mohammadzad Mehryar, Zhiping Teng and Yi Zeng
Med. Chem. Commun., 2014, Advance Article
DOI: 10.1039/C4MD00214H, Review Article

3,5-Diamino-1,2,4-triazoles as a novel scaffold for potent, reversible LSD1 (KDM1A) inhibitors
Craig J. Kutz, Steven L. Holshouser, Ethan A. Marrow and Patrick M. Woster
Med. Chem. Commun., 2014, Advance Article
DOI: 10.1039/C4MD00283K, Concise Article
From themed collection Epigenetics

Check out the following HOT articles, these have been made free to access for a limited time:

Recognition of diazirine-modified O-GlcNAc by human O-GlcNAcase
Andrea C. Rodriguez and Jennifer J. Kohler
Med. Chem. Commun., 2014,5, 1227-1234
DOI: 10.1039/C4MD00164H

Free to access until 21st August 2014

Evaluation of functional groups as acetyl-lysine mimetics for BET bromodomain inhibition
Phillip P. Sharp, Jean-Marc Garnier, David C. S. Huang and Christopher J. Burns
Med. Chem. Commun., 2014, Advance Article
DOI: 10.1039/C4MD00182F

Free to access until 21st August 2014

Beyond substrate analogues: new inhibitor chemotypes for glycosyltransferases
Lauren Tedaldi and Gerd K. Wagner
Med. Chem. Commun., 2014,5, 1106-1125
DOI: 10.1039/C4MD00086B

Free to access until 21st August 2014

Emerging classes of armed antibody therapeutics against cancer
Christian Hess, Dario Venetz and Dario Neri  
Med. Chem. Commun., 2014,5, 408-431
DOI: 10.1039/C3MD00360D

Free to access until 25th April

Cysteine-reactive chemical probes based on a modular 4-aminopiperidine scaffold
Shalise M. Couvertier and Eranthie Weerapana
Med. Chem. Commun., 2014,5, 358-362
DOI: 10.1039/C3MD00289F

Free to access until 25th April

Design, synthesis, and preliminary ex vivo and in vivo evaluation of cationic magnetic resonance contrast agent for rabbit articular cartilage imaging
Takayoshi Irie, Kazuhiro Oda, Akihiko Shiino, Mitsuhiko Kubo, Shigehiro Morikawa, Noboru Urushiyama, Shuji Aonuma, Takahide Kimura, Toshiro Inubushi, Toshitaka Oohashi and Naoki Komatsu  
Med. Chem. Commun., 2013, DOI: 10.1039/C3MD00229B

Free to access until 13th December

Small-molecule Inhibitors of SREBP Activation – Potential for New Treatment of Metabolic Disorders
Mizuki Watanabe and Motonari Uesugi  
Med. Chem. Commun., 2013, DOI: 10.1039/C3MD00177F

Free to access until 13th December