Focus on new talent
MedChemComm profiles the contributors to the New Talent themed issue
On the origins of
The ability of many drugs, unintended most often, to interact with multiple proteins is commonly referred to as polypharmacology. Could this be a reminiscent chemical signature of early protein evolution?
Small molecules aimed at type III secretion systems to inhibit bacterial virulence
The development of new anti-bacterial compounds presents a major challenge to modern medicine as bacterial strains resistant to traditional antibiotics are constantly emerging.
protein-coupled receptors in structure-based drug design: a case study with adenosine A2A receptor
The first example of structure-based drug design with stabilised GPCRs has enabled the identification of a preclinical candidate for the treatment of Parkinson's disease.
Approaches to discover non-ATP site kinase inhibitors
This review will highlight the most commonly used methods to discover small molecule Type III/IV kinase inhibitors.
Amino-derivatives of the sesquiterpene lactone class of natural products as prodrugs
The medicinal chemistry of amino-derivatives of the sesquiterpene lactones is described, beginning with synthetic development, moving into pharmacological applications, and finishing with clinical translation.
The status of type I polyketide synthase ketoreductases
The functional dissection of type I polyketide synthases has established that ketoreductases most commonly set the orientations of the hydroxyl and alkyl substituents of complex polyketides. Here we review the biochemical, structural biology, and engineering studies that have helped elucidate how stereocontrol is enforced by these enzymes.
Exploring the structural determinants of selective phosphopeptide recognition using bivalent metal-coordination complexes
We demonstrate that Lewis acidic coordination complexes equipped with cationic binding groups might be best utilized as selective receptors for binding phosphopeptides with anionic side chain residues proximal to the phosphorylated residue.
Experimental validation of in silico target predictions on synergistic
Two relatively recent trends have become apparent in current early stage drug discovery settings: firstly, a revival of phenotypic screening strategies and secondly, the increasing acceptance that some drugs work by modulating multiple targets in parallel (‘multi-target drugs’).
Mechanistic insight into inhibition of two-component system signaling
A scaffold that specifically interacts with the highly conserved ATP-binding domain in histidine kinases has been identified.
Interaction of long telomeric DNAs with macrocyclic hexaoxazole as a G-quadruplex ligand
The interactions of long telomeric DNAs, which mimic telomeres in living cells, with a macrocyclic hexaoxazole ligand L2H2-6OTD (2) were investigated by means of electrophoresis mobility shift assay, circular dichroism (CD) titration analysis, and DNA melting measurements.
Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1 – the discovery of AZD2353
Focus on ligand efficiency, ligand lipophilicity efficiency, and conformational restriction led to the discovery of AZD2353.
Identification of false positives in “HTS hits to lead”: The application of Bayesian models in HTS triage to rapidly deliver a series of selective TRPV4
The use of computational techniques to remove frequent hitters and enable the identification of a number of TRPV4 series from an HTS campaign will be described. The hit-to-lead efforts in one such series will also be discussed.
Structure–activity relationship studies using
peptide arrays: the example of HIV-1 Rev–integrase interaction
We used peptide arrays to perform structure–activity relationship studies on anti-HIV peptides derived from HIV-1 integrase.
polymerization of mannosyl tricyclic orthoesters: rationalising the stereo and regioselectivity of glycosidic bond formation using quantum chemical calculations
Quantum chemical methods have been used to assess the physico-chemical origin of the stereo and regio-selectivity during glycosyl tricyclic orthoester polymerization. The subtle modulation of steric and electronic factors dramatically influences the reaction.
Discovery and optimization of efficacious neutral 4-amino-6-biphenyl-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5-one diacylglycerol acyl transferase-1 (DGAT1) inhibitors
Neutral DGAT1 inhibitors have been designed with comparable pre-clinical efficacy and PK/PD to those previously described for acidic inhibitors.
The muraminomicin biosynthetic gene cluster and enzymatic formation of the 2-deoxyaminoribosyl appendage
The biosynthetic genes for muraminomicin F were uncovered, and the enzymatic synthesis of the unusual aminoribosyl appendage was delineated.
triazole-based TGR5 agonists towards orally available agents
With the challenge of striking the balance of TGR5 potency and clearance, the screening strategy as well as medicinal chemistry strategy are discussed in this article.
Gobichelin A and B: mixed-
ligand siderophores discovered using proteomics
PrISM (Proteomic Investigation of Secondary Metabolism), integrated with genomics and metabolomics, has led to the discovery of the new natural products, gobichelin A and B.
A monomeric form of iNOS can rationalise observed SAR for inhibitors of dimerisation: quantum mechanics and docking compared
Many interaction types bind iNOS and inhibitors of its dimerization: docking methods reproduce geometries and quantum mechanics lipophilicity ligand efficiencies.
Navigations of chemical space to further the understanding of polypharmacology in human nuclear receptors
The article analyses properties featuring the binding site of human nuclear receptors and cognate ligands, investigating aspects of polypharmacology.
Discovery of a highly selective FLT3 kinase
inhibitor from phenotypic cell viability profiling
We discovered a novel heterobiaryl pyrazolopyridine skeleton as a selective FLT3 inhibitor from phenotype-based viability profiling and hypothesis-driven deconvolution.
Two-in-one: a pH-sensitive,
acridine-based, fluorescent probe binds G-quadruplexes in oncogene promoters
We report the synthesis of an acridine-containing cyanine dye and demonstrate its potential as a pH-responsive colorimetric indicator and fluorescent probe.
histamine H4 receptor– ligand binding modes
Computational prediction of ligand binding modes in G protein-coupled receptors (GPCRs) remains a challenging task. Systematic consideration of different protein modelling templates, ligand binding poses, and ligand protonation states in extensive molecular dynamics (MD) simulation studies enabled the prediction of ligand-specific mutation effects in the histamine H4 receptor, a key player in inflammation.
Sulforaphane and erucin, natural isothiocyanates from broccoli, inhibit bacterial quorum sensing
Sulforaphane and erucin, two natural isothiocyanates that are highly abundant in broccoli and other cruciferous vegetables, were found to strongly inhibit quorum sensing and virulence in Pseudomonas aeruginosa.
Synthesis and evaluation of stable substrate analogs as potential modulators of cyclodiphosphate synthase IspF
Stable IspF substrate analogs display distinct and unexpected properties as modulators of IspF and IspF–MEP activities.
Design and synthesis of a novel series of cyclohexyloxy-pyridyl derivatives as inhibitors of diacylglycerol acyl transferase 1
Design and synthesis of a novel series of cyclohexyloxy-pyridyl inhibitors of diacylglycerol acyl transferase 1.
Phage display libraries of differently sized bicyclic peptides
Loop length variability in bicyclic peptide libraries increased the diversity of the motifs found in affinity selections towards the tumor-associated protease uPA.
Truncated militarinone fragments identified by total chemical synthesis induce neurite outgrowth
Short analogs of militarinone D were prepared that omit the configurationally unstable triene side chain bearing stereogenic centers and cut down the number of synthetic steps by 12. These short natural product fragments induce neuritogenesis at markedly lower concentrations.
Structure–activity relationship studies of miniproteins targeting the
androgen receptor–coactivator interaction
Miniproteins featuring a stable α-helical motif allow exploring point mutations in and around FXXLF motifs to improve androgen receptor affinity.
The design and synthesis of 5- and 6-isoxazolylbenzimidazoles as selective
inhibitors of the BET bromodomains
Simple 1-substituted 5- and 6-isoxazolyl-benzimidazoles have been shown to be potent inhibitors of the BET bromodomains with selectivity over the related bromodomain of CBP.
Discovery of hydroxamate bioisosteres as KAT II
inhibitors with improved oral bioavailability and pharmacokinetics
A series of kynurenine aminotransferase II (KAT II) inhibitors has been developed replacing the hydroxamate motif with a bioisostere.
Design of membrane targeting tobramycin-based cationic
amphiphiles with reduced hemolytic activity
Hemolysis caused by amphiphilic tobramycin antimicrobial agents is significantly reduced by altering the bond linking their hydrophobic and hydrophilic parts.
Inhibitors of bacterial tubulin target bacterial membranes in vivo
The loss of ΔΨ disrupts the normal localization pattern of membrane-associated proteins. The cartoon and images depict the diffuse pattern of a polarly localized protein, MinD after reduction of ΔΨ in E. coli. The length of the line across the cell membrane depicts the relative magnitude of ΔΨ.
On the importance of synthetic organic chemistry in
drug discovery: reflections on the discovery of antidiabetic agent ertugliflozin
The discovery of antidiabetic agent ertugliflozin is described. In this article, emphasis is placed on the critical role that organic synthesis played in influencing our medicinal chemistry strategy.
Optimisation of aqueous solubility in a series of G
protein coupled receptor 119 (GPR119) agonists
Solubility improvements in a series of GPR119 agonists are achieved through reduction of lipophilicity together with hydrogen bond acceptor modulation.
A mast cell degranulation screening assay for the identification of novel mast cell activating agents
A cell-based screen to identify novel mast cell activating compounds.
About this collection
New talents in Medicinal Chemistry. This issue will highlight medicinal chemistry research in its broadest sense, and showcase the strength of research being carried out by tomorrow's leaders in the field.
Articles in this themed issue will be added below as soon as possible after they are published. Please return to this page frequently to see the collection grow.