Prediction of hERG inhibition of drug discovery compounds using biomimetic HPLC measurements

The major causes of failure of drug discovery compounds in clinics are the lack of efficacy and toxicity. To reduce late-stage failures in the drug discovery process, it is essential to estimate early the probability of adverse effects and potential toxicity. Cardiotoxicity is one of the most often observed problems related to a compound\u27s inhibition of the hERG channel responsible for the potassium cation flux. Biomimetic HPLC methods can be used for the early screening of a compound\u27s lipophilicity, protein binding and phospholipid partition. Based on the published hERG pIC50 data of 90 marketed drugs and their measured biomimetic properties, a model has been developed to predict the hERG inhibition using the measured binding of compounds to alpha-1-acid-glycoprotein (AGP) and immobilised artificial membrane (IAM). A representative test set of 16 compounds was carefully selected. The training set, involving the remaining compounds, served to establish the linear model. The mechanistic model supports the hypothesis that compounds have to traverse the cell membrane and bind to the hERG ion channel to cause the inhibition. The AGP and the hERG ion channel show structural similarity, as both bind positively charged compounds with strong shape selectivity. In contrast, a good IAM partition is a prerequisite for cell membrane traversal. For reasons of comparison, a corresponding model was derived by replacing the measured biomimetic properties with calculated physicochemical properties. The model established with the measured biomimetic binding properties proved to be superior and can explain over 70% of the variance of the hERG pIC50 values

The Forty-Sixth Euro Congress on Drug Synthesis and Analysis: Snapshot

The 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017) was arranged within the celebration of the 65th Anniversary of the Faculty of Pharmacy at Comenius University in Bratislava, Slovakia from 5-8 September 2017 to get together specialists in medicinal chemistry, organic synthesis, pharmaceutical analysis, screening of bioactive compounds, pharmacology and drug formulations; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topic of the conference, Drug Synthesis and Analysis, meant that the symposium welcomed all pharmacists and/or researchers (chemists, analysts, biologists) and students interested in scientific work dealing with investigations of biologically active compounds as potential drugs. The authors of this manuscript were plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting

Separation and determination of organometallic compounds in the environment - speciation analysis

In the present Ph.D. thesis, analytical procedures for the separation and quantification of selenium species, selenites and selenates, selenomethionine, selenocystine, selonocystamine, selenourea, dimethylselenide and dimethyldiselenide were developed. Furthermore, by studying theIR lipophilicity, it was found that they are not likely to bioaccumulate by passive diffusion. Finally, leaching procedures for the extraction of arsenic species from SOLID matrices were developed, while the separation of dibutylitin from triphenyltin was achieved. After their validatioN, the developed techniques were successfully applied to environmental and biological samples.Στα πλαίσια της παρούσας διατριβής αναπτύχθηκαν αναλυτικές τεχνικές ΓΙΑ ΤΟΝ διαχωρισμο και ΤΟΝ ποσοτικο προσδιορισμο ΤΩΝ είδΩΝ σεληνίου σεληνιώδΩΝ και σεληνικΩΝ ιόντΩΝ, σεληνομεθειονίνηΣ, σεληνοκυστίνηΣ, σεληνοκυσταμίνηΣ, σεληνουρίαΣ, διμεθυλοσεληνίδιοΥ και διμεθυλοδισεληνίδιοΥ. τα παραπάνω είδη δεν ΔΙΑΠΙΣΤΩΘΗΚΕ να παρουσιάζουν τάσΗ βιοσυσσώρευσης με μηχανισμό παθητικής διάχυσης. ΕπιΣΗς, αναπτύχθηκαν μέθοδοι παραλαβής ενώσεων αρσενικού από στερεούς φορείς και διαχωρισμός του διβουτυλικού από τον τριφαινυλικό κασσίτερο. οι αναπτυχθείσες τεχνικές ΕΛΕΓΧΘΗΚΑΝ Ως προς ΤΗΝ ΕΓΚΥΡΟΤΗΤΑ τους ΚΑΙ εφαρμόσθηκαν με επιτυχία σε περιβαλλοντικά και βιολογικά δείγματα

Prediction Models for Brain Distribution of Drugs Based on Biomimetic Chromatographic Data

The development of high-throughput approaches for the valid estimation of brain disposition is of great importance in the early drug screening of drug candidates. However, the complexity of brain tissue, which is protected by a unique vasculature formation called the blood-brain barrier (BBB), complicates the development of robust in silico models. In addition, most computational approaches focus only on brain permeability data without considering the crucial factors of plasma and tissue binding. In the present study, we combined experimental data obtained by HPLC using three biomimetic columns, i.e., immobilized artificial membranes, human serum albumin, and alpha(1)-acid glycoprotein, with molecular descriptors to model brain disposition of drugs. K-p,K-uu,K-brain, as the ratio between the unbound drug concentration in the brain interstitial fluid to the corresponding plasma concentration, brain permeability, the unbound fraction in the brain, and the brain unbound volume of distribution, was collected from literature. Given the complexity of the investigated biological processes, the extracted models displayed high statistical quality (R-2 > 0.6), while in the case of the brain fraction unbound, the models showed excellent performance (R-2 > 0.9). All models were thoroughly validated, and their applicability domain was estimated. Our approach highlighted the importance of phospholipid, as well as tissue and protein, binding in balance with BBB permeability in brain disposition and suggests biomimetic chromatography as a rapid and simple technique to construct models with experimental evidence for the early evaluation of CNS drug candidates

Synthesis, Bioactivity, Pharmacokinetic and Biomimetic Properties of Multi-Substituted Coumarin Derivatives

A series of novel multi-substituted coumarin derivatives were synthesized, spectroscopically characterized, and evaluated for their antioxidant activity, soybean lipoxygenase (LOX) inhibitory ability, their influence on cell viability in immortalized human keratinocytes (HaCaT), and cytotoxicity in adenocarcinomic human alveolar basal epithelial cells (A549) and human melanoma (A375) cells, in vitro. Coumarin analogues 4a–4f, bearing a hydroxyl group at position 5 of the coumarin scaffold and halogen substituents at the 3-phenyl ring, were the most promising ABTS•+ scavengers. 6,8-Dibromo-3-(4-hydroxyphenyl)-4-methyl-chromen-2-one (4k) and 6-bromo-3-(4,5-diacetyloxyphenyl)-4-methyl-chromen-2-one (3m) exhibited significant lipid peroxidation inhibitory activity (IC50 36.9 and 37.1 μM). In the DCF-DA assay, the 4′-fluoro-substituted compound 3f (100%), and the 6-bromo substituted compounds 3i (80.9%) and 4i (100%) presented the highest activity. The 3′-fluoro-substituted coumarins 3e and 4e, along with 3-(4-acetyloxyphenyl)-6,8-dibromo-4-methyl-chromen-2-one (3k), were the most potent lipoxygenase (LOX) inhibitors (IC50 11.4, 4.1, and 8.7 μM, respectively) while displaying remarkable hydroxyl radical scavenging ability, 85.2%, 100%, and 92.9%, respectively. In silico docking studies of compounds 4e and 3k, revealed that they present allosteric interactions with the enzyme. The majority of the analogues (100 μΜ) did not affect the cell viability of HaCaT cells, though several compounds presented over 60% cytotoxicity in A549 or A375 cells. Finally, the human oral absorption (%HOA) and plasma protein binding (%PPB) properties of the synthesized coumarins were also estimated using biomimetic chromatography, and all compounds presented high %HOA (>99%) and %PPB (60–97%) values