Toward structure-based drug design against the epidermal growth factor receptor (EGFR).

Most of the available crystal structures of epidermal growth factor receptor (EGFR) kinase domain, bound to drug inhibitors, originated from ligand-based drug design studies. Here, we used variations in 110 crystal structures to assemble eight distinct families highlighting the C-helix orientation in the N-lobe of the EGFR kinase domain. The families shared similar mutational profiles and similarity in the ligand R-groups (chemical composition, geometry, and charge) facing the C-helix, mutation sites, and DFG domain. For structure-based drug design, we recommend a systematic decision-making process for choice of template, guided by appropriate pairwise fitting and clustering before the molecular docking step. Alternatively, the binding site shape/volume can be used to filter and select the compound libraries.

Direct fluorogenic detection of palladium and platinum organometallic complexes with proteins and nucleic acids in polyacrylamide gels.

Allyl- and propargyl ethers of umbelliferone are sensitive probes for palladium and platinum, including anticancer compounds cisplatin, carboplatin and oxaliplatin, and effective for direct visualization of protein and DNA complexes with organometallic compounds in polyacrylamide gels allowing easy detection of interactions with analyzed protein or nucleic acid. Both probes can be used for fast evaluation of Pd/Pt binding to nanocarriers relevant in drug targeted therapy or specific clinically relevant target macromolecules.

Detergent-modified catalytic and enzymomimetic activity of silver and palladium nanoparticles biotemplated by Pyrococcus furiosus ferritin.

Palladium and silver nanoparticles (NPs) anchored at the outer surface of ferritin form stable suspension of non-coated particles that possess several catalytic and enzymomimetic activities. These activities are strongly affected by detergents that significantly influence the reaction efficiency and specificity. Reductive dehalogenation of various azo dye substrates shows strong differences in reactivity for each substrate-detergent pair. Reductive dehalogenation is negatively influenced by cationic detergents while catalytic depropargylation is severely impaired by polyethylene oxide containing detergents that is an important finding in respect to potential biorthogonal applications. Moreover, Suzuki-Miyaura reaction is promoted by polyethylene oxide containing detergents but some of them also facilitate dehalogenation. Enzymomimetic peroxidase activity of silver NPs can be detected only in presence of sodium dodecyl sulfate (SDS) while peroxidase activity of palladium NPs is enhanced by SDS and sodium deoxycholate.

Examination of α-exosite inhibitors against Botulinum neurotoxin A protease through structure-activity relationship studies of chicoric acid.

Botulinum neurotoxins (BoNT) are among the most toxic known substances and currently there are no effective treatments for intraneuronal BoNT intoxication. Chicoric acid (ChA) was previously reported as a BoNT/A inhibitor that binds to the enzyme's α-exosite. Herein, we report the synthesis and structure-activity relationships (SARs) of a series of ChA derivatives, which revealed essential binding interactions between ChA and BoNT/A. Moreover, several ChA-based inhibitors with improved potency against the BoNT/A were discovered.

The Use of the Er:YAG Laser for Bracket Debonding and Its Effect on Enamel Damage.

OBJECTIVE: The aim of the study was to evaluate the influence of Er:YAG laser irradiation on the debonding of metal and ceramic brackets and enamel damage ex vivo. BACKGROUND DATA: The principle of safe bracket debonding is to degrade the adhesive resin strength connecting the tooth and bracket. Removal of adhesive resin from tooth surfaces without iatrogenic damage (enamel loss) is generally the main problem of the otherwise very successful method of aesthetic straightening of teeth. METHODS: Forty ceramic and metal brackets (Clarity™ Advanced and Victory Series™; 3M Unitek, Monrovia, CA) were standardly bonded to buccal polished enamel surfaces of 30 caries-free human third molars. Two types of adhesive resins (Transbond™ XT Light Cure Adhesive; 3M Unitek, and Variolink II Professional Set; Ivoclar Vivadent AG) were used. Before debonding, the brackets in the laser group were irradiated with the Er:YAG laser (FJFI CVUT) 280 mJ, 250 µs long, repetition rate 6 Hz, spot focus 1 mm, and 140 sec. The control group was debonded without the laser irradiation. During the bracket irradiation, temperature changes inside the tooth were monitored using a thermal image infrared camera. The enamel surface was investigated by SEM. RESULTS: It has been observed that bracket removal was easier after the Er:YAG laser irradiation, and temperature rise was limited (from 2.0°C to 3.2°C) also for metal brackets. As against the nonirradiated samples, SEM investigation has confirmed no damage to enamel. CONCLUSIONS: Irradiation with Er:YAG laser radiation before debonding of ceramic brackets significantly decreases the bonding failure and amount of remaining adhesive.

Toward the discovery of dual inhibitors for botulinum neurotoxin A: concomitant targeting of endocytosis and light chain protease activity.

Dyngo-4a™ has been found to be an endocytic inhibitor of BoNT/A neurotoxicity through dynamin inhibition. Herein, we demonstrate this molecule to have a previously unrecognized dual activity against BoNT/A, dynamin-protease inhibition. To establish the importance of this dual activity, detailed kinetic analysis of Dyngo-4a's inhibition of BoNT/A metalloprotease as well as cellular and animal toxicity studies have been described. The research presented is the first polypharmacological approach to counteract BoNT/A intoxication.

Organocatalytic preparation of substituted cyclopentanes: a mechanistic study.

The reaction mechanism of a tandem conjugate addition/α-alkylation of enals leading to functionalized cyclopentanes catalyzed by O-trimethylsilyldiphenylprolinol was investigated by mass spectrometry, NMR spectroscopy, and DFT calculations. We have shown that the high stereoselectivity of the reaction depends on the energy discrimination between the two stereoisomers formed by the condensation of the α,ß-unsaturated aldehyde (cinnamaldehyde) and the catalyst. The stereoselectivity of this step depends on the solvent used. The experimental activation barriers were determined to be E(a) = 25 ± 7 kJ mol(-1) (Arrhenius equation), ΔH(‡) = 23 ± 7 kJ mol(-1), and ΔG(‡) = 101 ± 9 kJ mol(-1) (Eyring equation).

Gas-phase fragmentation of deprotonated p-hydroxyphenacyl derivatives.

Electrospray ionization of methanolic solutions of p-hydroxyphenacyl derivatives HO-C(6)H(4)-C(O)-CH(2)-X (X = leaving group) provides abundant signals for the deprotonated species which are assigned to the corresponding phenolate anions (-)O-C(6)H(4)-C(O)-CH(2)-X. Upon collisional activation in the gas phase, these anions inter alia undergo loss of a neutral "C(8)H(6)O(2)" species concomitant with formation of the corresponding anions X(-). The energies required for the loss of the neutral roughly correlate with the gas phase acidities of the conjugate acids (HX). Extensive theoretical studies performed for X = CF(3)COO in order to reveal the energetically most favorable pathway for the formation of neutral "C(8)H(6)O(2)" suggest three different routes of similar energy demands, involving a spirocyclopropanone, epoxide formation, and a diradical, respectively.