Deep Learning Enables Automatic Correction of Experimental HDX-MS Data with Applications in Protein Modeling

Observed mass shifts associated with deuterium incorporation in hydrogen–deuterium exchange mass spectrometry (HDX-MS) frequently deviate from the initial signals due to back and forward exchange. In typical HDX-MS experiments, the impact of these disparities on data interpretation is generally low because relative and not absolute mass changes are investigated. However, for more advanced data processing including optimization, experimental error correction is imperative for accurate results. Here the potential for automatic HDX-MS data correction using models generated by deep neural networks is demonstrated. A multilayer perceptron (MLP) is used to learn a mapping between uncorrected HDX-MS data and data with mass shifts corrected for back and forward exchange. The model is rigorously tested at various levels including peptide level mass changes, residue level protection factors following optimization, and ability to correctly identify native protein folds using HDX-MS guided protein modeling. AI is shown to demonstrate considerable potential for amending HDX-MS data and improving fidelity across all levels. With access to big data, online tools may eventually be able to predict corrected mass shifts in HDX-MS profiles. This should improve throughput in workflows that require the reporting of real mass changes as well as allow retrospective correction of historic profiles to facilitate new discoveries with these data

Investigation of inhibition of human glucose 6-phosphate dehydrogenase by some 99mTc chelators by <i>in silico</i> and <i>in vitro</i> methods

Charles University, Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Author: Hana Beránková Supervisor: PharmDr. Miroslav Kovařík, PhD. Title of the thesis: Evaluation of diet composition by questionnaire method Theoretical introduction and aim of the thesis: Although there are a number of guaranteed good practices and definitions for healthy eating and the amount of recieved nutrients is a totally individual matter, in general we can say it is mainly a balanced amount of essential nutrients (carbohydrates, proteins, lipids), additional nutrients (vitamins and minerals) and sufficient amount of water that keeps the human body in stable homeostasis. The aim of this thesis was to get an overview of this issue and to focus on practical research consisting in monitoring of nutritional intake of energy, nutrients, vitamins and minerals in a selected group of people and in the end to compare the results with the recommended values. Methods: Testing took place in the form of weekly records of all food intake and physical activity in a group of randomly selected persons aged 20-30. The study was conducted from March to May 2018. The data were processed by NutriDan computer program and with using Compendium of physical activities from 2011. Results: The results of such...Univerzita Karlova, Farmaceutická fakulta v Hradci Králové Katedra biologických a lékařských věd Student: Bc. Hana Beránková Školitel: PharmDr. Miroslav Kovařík, PhD. Název diplomové práce: Hodnocení kompozice stravy dotazníkovou metodou Teoretický úvod a cíle: Ačkoliv existuje celá řada zaručených správných postupů a definic pro zdravé stravování a množství přijatých živin je zcela individuální záležitost, obecně lze říci, že jde především o vyvážené množství základních živin (sacharidy, proteiny, lipidy), doplňkových živin (vitamíny a minerály) a dostatečné množství vody, které udržuje lidský organismus ve stabilní homeostázi. Cílem této práce bylo získat přehled v této problematice a zaměřit se na praktický výzkum spočívající ve sledování nutričního příjmu energie, živin, vitaminů a minerálních látek u vybrané skupiny osob a v závěru porovnat zjištěné hodnoty s těmi doporučenými. Metody: Testování probíhalo formou týdenních záznamů veškeré přijaté potravy a fyzické činnosti u skupiny náhodně vybraných osob ve věku 20-30 let. Studie probíhala v období od března do května 2018. Data byla zpracována pomocí počítačového programu NutriDan a tabulek Compendium of physical activities z roku 2011. Výsledky: Výsledné hodnoty ukázaly, že energetický výdej většinou převažoval příjem, proto byla...Department of Biological and Medical SciencesKatedra biologických a lékařských vědFarmaceutická fakulta v Hradci KrálovéFaculty of Pharmacy in Hradec Králov

Kinetic and docking studies of cytosolic/tumor-associated carbonic anhydrase isozymes I, II and IX with some hydroxylic compounds

WOS: 000385270300044PubMed ID: 26634620A series of hydroxylic compounds (1-10, NK-154 and NK-168) have been assayed for the inhibition of three physiologically relevant carbonic anhydrase isozymes, the cytosolic isozymes I, II and tumor-associated isozyme IX. The investigated compounds showed inhibition constants in the range of 0.068-4003, 0.012-9.9 and 0.025-115 mm at the hCA I, hCA II and hCA IX enzymes, respectively. In order to investigate the binding mechanisms of these inhibitors, in silico studies were also applied. Molecular docking scores of the studied compounds are calculated using scoring algorithms, namely Glide/induced fit docking. The inhibitory potencies of the novel compounds were analyzed at the human isoforms hCA I, hCA II and hCA IX as targets and the K-I values were calculated.TUBITAK (The Scientific and Technological Research Council of Turkey)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114Z731]; Ege UniversityEge University [2011 Fen 050]; Ondokuz Mayis University Scientific Research Projects CouncilOndokuz Mayis University [2013/PYO.ZRT.1901.13.004]This study was financed by TUBITAK (The Scientific and Technological Research Council of Turkey) (Project no: 114Z731) for (MS), Ege University (Scientific Research Project 2011 Fen 050) for (NK and DA) and Ondokuz Mayis University Scientific Research Projects Council (Project no: 2013/PYO.ZRT.1901.13.004) for (DE). The authors report no conflicts of interest

Integration of multi-scale molecular modeling approaches with experiments for the in silico guided design and discovery of novel hERG-Neutral antihypertensive oxazalone and imidazolone derivatives and analysis of their potential restrictive effects on cell proliferation

AT1 antagonists is the most recent drug class of molecules against hypertension and they mediate their actions through blocking detrimental effects of angiotensin II (A-II) when acts on type I (AT1) A-II receptor. The effects of AT1 antagonists are not limited to cardiovascular diseases. AT1 receptor blockers may be used as potential anti-cancer agents - due to the inhibition of cell proliferation stimulated by A-II. Therefore, AT1 receptors and the A-II biosynthesis mechanisms are targets for the development of new synthetic drugs and therapeutic treatment of various cardiovascular and other diseases. In this work, multi-scale molecular modeling approaches were performed and it is found that oxazolone and imidazolone derivatives reveal similar/better interaction energy profiles compared to the FDA approved sartan molecules at the binding site of the AT1 receptor. In silico-guided designed hit molecules were then synthesized and tested for their binding affinities to human AT1 receptor in radioligand binding studies, using [I-125-Sar(1)-Ile(8)] AngII. Among the compounds tested, 19d and 9j molecules bound to receptor in a dose response manner and with relatively high affinities. Next, cytotoxicity and wound healing assays were performed for these hit molecules. Since hit molecule 19d led to deceleration of cell motility in all three cell lines (NIH3T3, A549, and H358) tested in this study, this molecule is investigated in further tests. In two cell lines (HUVEC and MCF-7) tested, 19d induced G2/M cell cycle arrest in a concentration dependent manner. Adherent cells detached from the plates and underwent cell death possibly due to apoptosis at 19d concentrations that induced cell cycle arrest. (C) 2017 Elsevier Masson SAS. All rights reserved