Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans

Geographically weighted elastic net logistic regression

This paper develops a localized approach to elastic net logistic regression, extending previous research describing a localized elastic net as an extension to a localized ridge regression or a localized lasso. All such models have the objective to capture data relationships that vary across space. Geographically weighted elastic net logistic regression is first evaluated through a simulation experiment and shown to provide a robust approach for local model selection and alleviating local collinearity, before application to two case studies: county-level voting patterns in the 2016 USA presidential election, examining the spatial structure of socio-economic factors associated with voting for Trump, and a species presence–absence data set linked to explanatory environmental and climatic factors at gridded locations covering mainland USA. The approach is compared with other logistic regressions. It improves prediction for the election case study only which exhibits much greater spatial heterogeneity in the binary response than the species case study. Model comparisons show that standard geographically weighted logistic regression over-estimated relationship non-stationarity because it fails to adequately deal with collinearity and model selection. Results are discussed in the context of predictor variable collinearity and selection and the heterogeneities that were observed. Ongoing work is investigating locally derived elastic net parameters

Plasma protein binding of prednisolone in normal volunteers and arthritic patients

The plasma binding of prednisolone was studied in twenty normal volunteers and twenty rheumatoid arthritis patients. An in vitro assessment of the binding following the addition of prednisolone, prednisone, and hydrocortisone to the plasmas obtained from the subjects showed significant differences in the percentage of prednisolone bound. However, the differences observed were regarded as clinically insignificant. The plasma protein binding was determined by an in vitro equilibrium dialysis of the individual plasma samples at 37° C. Prednisolone levels on both sides of the dialysis membrane were determined using radioactivity and HPLC analytical methodologies. The percentages of prednisolone bound calculated from the analytical results of either the radiochemical or HPLC method were not significantly different. The change in the percentage of prednisolone bound to plasma proteins was studied as a function of the total prednisolone plasma concentration in a normal volunteer and in a systemic lupus erythematosis patient. As a result of prednisolone binding to both transcortin and albumin, the binding of prednisolone changes as a function of prednisolone concentration. The binding data were fitted using nonlinear least squares regression, and the affinity constants for the binding of prednisolone to transcortin and albumin were estimated.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46638/1/228_2004_Article_BF00568200.pd

Overlapping pK a of the Multiprotic Hemostyptic Eltrombopag using UV–Vis Multiwavelength Spectroscopy and Potentiometry

pH-potentiometric and WApH-spectrophotometric titrations of the multiprotic hemostyptic Eltrombopag for dissociation constants determination were compared. Hemostyptic and hemostatic Eltrombopag treats low blood platelet counts in adults with chronic immune idiopathic thrombocytopenia ITP. Eltrombopag exhibits five protonatable sites in a pH range of 2 to 10, where only two pK are well separated (ΔpK > 3), while the other three are near dissociation constants of overlapping equilibria. According to MARVIN prediction, in the neutral medium Eltrombopag occurs in the slightly water soluble form LH3 that can be protonated to the soluble species LH4 and LH5 The molecule LH3 can be dissociated to still difficultly soluble species LH2, LH and L. Due to limited solubility of Eltrombopag above pH 9.5 the protonation was studied up to pH 10. Five dissociation constants can be reliably determined with REACTLAB and SQUAD84 leading to the same value. From a dependence on ionic strength the thermodynamic dissociation constants were estimated at 25°C: pKa1T = 2.69, pKa2T = 6.97, pKa3T = 7.13, pKa4T = 7.65, pKa5T = 8.30. Since pH above 10 and pH down 5 occurs in a titrated solution the very fine precipitate of Eltrombopag which is initially forming a slight opalescence, this part of the potentiometric titration curve pH over 9 and pH below 5 was not taken into regression analysis to estimate pKa2 = 6.53(01), pKa3 = 7.60(04), pKa4 = 9.62(59), pKa5 = 10.55(340) at 25°C with ESAB and HYPERQUAD.Byly porovnávány potenciometrické hodnoty pH a WApH spektrofotometrické titrace multiprotického hemostyptického Eltrombopagu pro stanovení disociačních konstant. Hemostyptický a hemostatický Eltrombopag léčí nízké počty krevních destiček u dospělých pacientů s chronickou imunitní idiopatickou trombocytopenií ITP. Eltrombopag vykazuje pět protonovatelných míst v rozmezí pH od 2 do 10, kde jsou jen dva pK dobře oddělené (ΔpK> 3), zatímco ostatní tři jsou téměř disociační konstanty překrývající se rovnováhy. Podle predikce společnosti MARVIN se v neutrálním prostředí Eltrombopag vyskytuje ve formě lehce rozpustné ve vodě LH3, která může být protonována na rozpustné druhy LH4 a LH5. Molekula LH3 může být disociována na stále obtížně rozpustné druhy LH2, LH a L. Vzhledem k omezenému rozpustnosti Eltrombopagu nad pH 9,5 byla zkoumána protonace až na pH 10. Pět disociačních konstant může být spolehlivě stanoveno pomocí REACTLAB a SQUAD84, což vede k stejné hodnotě. Ze závislosti na iontové síle byly termodynamické disociační konstanty odhadnuty na 25 ° C: pKa1T = 2,69, pKa2T = 6,97, pKa3T = 7,13, pKa4T = 7,65, pKa5T = 8,30. Vzhledem k tomu, že pH v hodnotě nad 10 a pH 5 se vyskytuje v titrovaném roztoku, velmi jemná sraženina Eltrombopagu, která zpočátku vytváří mírnou opalescenci, tato část potenciometrické titrační křivky pH nad 9 a pH pod 5 nebyla převzata do regresní analýzy k odhadu pKa2 = 6,53 (01), pKa3 = 7,60 (04), pKa4 = 9,62 (59), pKa5 = 10,55 (340) při 25 ° C pomocí ESAB a HYPERQUAD