ChemMedChem

The cover picture shows the putative binding mode of cyclotheonamide A along the active-site cleft of subunit A of the β-tryptase homotetramer (top), a serine protease with trypsin-like activity that has been the focus of interest as a promising new drug target in the treatment of asthma. Based on this model, the cyclotheonamide E4 scaffold was modified in two ways (indicated in orange) to give potent and selective β-tryptase inhibitors that bind reversibly to the protein (bottom). For more details, see the Communication by N. Schaschke and C. P. Sommerhoff on p. 367 ff.

The inside cover picture shows the X-ray structure of viscumin as surface representation (PBD code: 1PUM), with a schematic perspective of the methods employed to screen a small library of lactose derivatives as viscumin ligands with increased affinity. The protocol strategically combines different experimental techniques, including organic synthesis and STD-NMR with solid-phase and cell-based assays. For more details, see the Full Paper by J. Jiménez-Barbero et al. on p. 415 ff.

Harnessing RNA interference: This review critically summarizes the use of chemical modifications employed in siRNAs by taking into account the structural and biochemical studies of Argonaute–RNA complexes. The major challenges associated with siRNA therapeutics are discussed, and a set of guidelines have been formulated to address these issues.

High potential! Despite the potentially harmful electrophilic character, α,β-unsaturated carbonyls are an important moiety in drug development. The special structural layout of this functionality allows the fine tuning of numerous properties, in particular, Michael acceptor activity, leading to potentially useful therapeutic agents.

FAAH inhibitors: This study identifies a new class of enol carbamates as potent, reversible inhibitors of fatty acid amide hydrolase (FAAH), endowed with high selectivity towards this target over other components of the endocannabinoid system.

Oxa-aza spiro compounds: In silico techniques were successfully employed to predict the rank order of derivatives based on their binding affinities to the monoamine transporters, SERT, NET and DAT. The proposed scaffolds derived from the pharmacophore model were experimentally evaluated in vitro and in vivo. A new class of selective “triple” re-uptake inhibitors was discovered, that may be developed further to give novel antidepressant agents.

Structural modification at two positions is the key: Cyclotheonamide E4 unspecifically blocks trypsin-like serine proteases in a covalent fashion. We converted this compound into a reversibly binding, potent and selective β-tryptase inhibitor.

The NPS–NPSR system regulates such biological functions as the sleep–wake cycle, locomotion, arousal, anxiety, and food intake. Polymorphisms of this receptor are also associated with asthma and allergies. This work presents the first structural study of the NPS receptor and simulation of the binding modes of nonpeptide antagonists.

Computer-based drug design was applied to systematically develop second-generation lead compounds for the improved inhibition of fructose 1,6-bisphosphatase. The selected compounds were synthesized, and their biological potency was determined by in vitro assays.

An accurate 3D model of CACYP51 was built by ligand-supported homology modeling. The active site was characterized by MCSS calculations, which led to the discovery of novel azoles with excellent in vitro antifungal activity.

PRMT inhibitors: The bis-carboxylic acid derivatives 1 b (yellow) and 7 b (green), shown here docked into the active site of protein arginine N-methyltransferase 1 (PRMT1), are disclosed as effective inhibitors of this enzyme, both in vitro and in vivo. These carboxy analogues are comparable or even better PRMT inhibitors compared with arginine methyltransferase inhibitor 1 (AMI-1; magenta), and they are practically inactive against the lysine methyltransferase SET7/9.

Carbohydrate chemistry: Sugar-binding proteins, lectins, are an increasingly valid target in drug design with growing awareness of the biological importance of glycans. A series of modified lactosides containing aromatic aglycan moieties were tested in a plant toxin model for their ability to block lectin binding to cell-surface glycans and consequently prevent the uptake of the plant toxin by the cell.

A combretastatin A-4 analogous thioanisyl oxazole shows superior cytotoxicity in human cancer cells. It is efficacious against HL-60 leukemia and 518A2 melanoma cells at picomolar IC₅₀ values and even against resistant HT-29 colon carcinoma cells at submicromolar IC₅₀ values. Its mode-of-action is associated with an upregulation of p21^cip1/waf1 and S/G₂ cell-cycle arrest.

A fragment-based approach applied to complex protein–protein interactions delivers suitable hits for optimization programs. Selection of fragments by virtual screening followed by NMR validation yielded a number of weak inhibitors of the S100B–p53 interaction. Competition studies and X-ray crystallography confirmed the binding mode of SEN205, a weak hit with the potential for optimization into a cancer therapeutic.

Use-dependency and recovery from hERG channel block by a small set of newly synthesized propafenone derivatives was tested to gain insight into their behavior with respect to trapping and non-trapping. Ligand–protein docking into homology models of the closed and open state of the hERG channel provides initial evidence for the molecular basis of drug trapping.

Nanomolar inhibitors of plasmepsin II and IV featuring a pyrrolidine scaffold have been discovered. Existing crystal structures were considered in order to generate reasonable binding modes. Because plasmepsins are highly flexible proteins and several findings could not be explained by the available crystal structures, molecular dynamics simulations were performed to assist in binding mode analysis.

To achieve a consensus model of hERG we tested seven models based on different S5 alignments by using a combination of static assessment, MD simulations, and docking. Model 6 fulfills all quality criteria and is confirmed by recent mutagenesis experiments.

Silver nanoparticles accelerate wound healing by mediating various effects on skin cells. The use of silver nanoparticles (AgNPs) for the treatment of skin wounds has gained popularity. In this study, we show that when applied to a skin wound, AgNPs can produce differential effects on keratinocytes and fibroblasts to have an overall positive outcome. This new finding provides further insight into the biological action of AgNPs.

Wiley-VCH, Weinheim 2009. 533 pp., hardcover € 149.00.—ISBN 978-3-52732-331-9

Wiley-VCH, Weinheim 2009. 356 pp., hardcover € 126.00.—ISBN 978-3-90639-056-7

Humana Press, Totowa 2009, VIII+172 pp., hardcover $ 159.00.—ISBN 978-1-60327-266-7