Browsing by Subject "DRUG DISCOVERY"

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  • Guo, Hui; Liu , Dongmei; Gao , Bin; Zhang, Xiaohui; You, Minli; Ren, Hui; Zhang, Hongbo; Almeida Santos, Helder; Xu , Feng (2016)
    Evodiamine (EVO) and rutaecarpine (RUT) are promising anti-tumor drug candidates. The evaluation of the anti-proliferative activity and cellular uptake of EVO and RUT in 3D multicellular spheroids of cancer cells would better recapitulate the native situation and thus better reflect an in vivo response to the treatment. Herein, we employed the 3D culture of MCF-7 and SMMC-7721 cells based on hanging drop method and evaluated the anti-proliferative activity and cellular uptake of EVO and RUT in 3D multicellular spheroids, and compared the results with those obtained from 2D monolayers. The drugs’ IC50 values were significantly increased from the range of 6.4–44.1 μM in 2D monolayers to 21.8–138.0 μM in 3D multicellular spheroids, which may be due to enhanced mass barrier and reduced drug penetration in 3D models. The fluorescence of EVO and RUT was measured via fluorescence spectroscopy and the cellular uptake of both drugs was characterized in 2D tumor models. The results showed that the cellular uptake concentrations of RUT increased with increasing drug concentrations. However, the EVO concentrations uptaken by the cells showed only a small change with increasing drug concentrations, which may be due to the different solubility of EVO and Rut in solvents. Overall, this study provided a new vision of the anti-tumor activity of EVO and RUT via 3D multicellular spheroids and cellular uptake through the fluorescence of compounds.
  • Brandt, Claudia; Seja, Patricia; Töllner, Kathrin; Römermann, Kerstin; Hampel, Philip; Kalesse, Markus; Kipper, Andi; Feit, Peter W.; Lykke, Kasper; Toft-Bertelsen, Trine Lisberg; Paavilainen, Pauliina; Spoljaric, Inkeri; Puskarjov, Martin; MacAulay, Nanna; Kaila, Kai; Löscher, Wolfgang (2018)
    Based on the potential role of Na-K-Cl cotransporters (NKCCs) in epileptic seizures, the loop diuretic bumetanide, which blocks the NKCC1 isoforms NKCC1 and NKCC2, has been tested as an adjunct with phenobarbital to suppress seizures. However, because of its physicochemical properties, bumetanide only poorly penetrates through the blood-brain barrier. Thus, concentrations needed to inhibit NKCC1 in hippocampal and neocortical neurons are not reached when using doses (0.1-0.5 mg/kg) in the range of those approved for use as a diuretic in humans. This prompted us to search for a bumetanide derivative that more easily penetrates into the brain. Here we show that bumepamine, a lipophilic benzylamine derivative of bumetanide, exhibits much higher brain penetration than bumetanide and is more potent than the parent drug to potentiate phenobarbital's anticonvulsant effect in two rodent models of chronic difficult-to-treat epilepsy, amygdala kindling in rats and the pilocarpine model in mice. However, bumepamine suppressed NKCC1-dependent giant depolarizing potentials (GDPs) in neonatal rat hippocampal slices much less effectively than bumetanide and did not inhibit GABA-induced Ca2+ transients in the slices, indicating that bumepamine does not inhibit NKCC1. This was substantiated by an oocyte assay, in which bumepamine did not block NKCC1a and NKCC1b after either extra- or intracellular application, whereas bumetanide potently blocked both variants of NKCC1. Experiments with equilibrium dialysis showed high unspecific tissue binding of bumetanide in the brain, which, in addition to its poor brain penetration, further reduces functionally relevant brain concentrations of this drug. These data show that CNS effects of bumetanide previously thought to be mediated by NKCC1 inhibition can also be achieved by a close derivative that does not share this mechanism. Bumepamine has several advantages over bumetanide for CNS targeting, including lower diuretic potency, much higher brain permeability, and higher efficacy to potentiate the anti-seizure effect of phenobarbital.
  • Humisto, Anu; Herfindal, Lars; Jokela, Jouni; Karkman, Antti; Bjørnstad, Ronja; Choudhury, Romi R.; Sivonen, Kaarina (2015)
    Cyanobacteria are an inspiring source of bioactive secondary metabolites. These bioactive agents are a diverse group of compounds which are varying in their bioactive targets, the mechanisms of action, and chemical structures. Cyanobacteria from various environments, especially marine benthic cyanobacteria, are found to be rich sources for the search for novel bioactive compounds. Several compounds with anticancer activities have been discovered from cyanobacteria and some of these have succeeded to enter the clinical trials. Varying anticancer agents are needed to overcome increasing challenges in cancer treatments. Different search methods are used to reveal anticancer compounds from natural products, but cell based methods are the most common. Cyanobacterial bioactive compounds as agents against acute myeloid leukemia are not well studied. Here we examined our new results combined with previous studies of anti-leukemic compounds from cyanobacteria with emphasis to reveal common features in strains producing such activity. We report that cyanobacteria harbor specific anti-leukemic compounds since several studied strains induced apoptosis against AML cells but were inactive against non-malignant cells like hepatocytes. We noted that particularly benthic strains from the Baltic Sea, such as Anabaena sp., were especially potential AML apoptosis inducers. Taken together, this review and re-analysis of data demonstrates the power of maintaining large culture collections for the search for novel bioactivities, and also how anti-AML activity in cyanobacteria can be revealed by relatively simple and low-cost assays.
  • Välimäki, Mika J.; Tölli, Maria A.; Kinnunen, Sini M.; Aro, Jani; Serpi, Raisa; Pohjolainen, Lotta; Talman, Virpi; Poso, Antti; Ruskoaho, Heikki J. (2017)
    Transcription factors are pivotal regulators of gene transcription, and many diseases are associated with the deregulation of transcriptional networks. In the heart, the transcription factors GATA4 and NKX2-5 are required for cardiogenesis. GATA4 and NKX2-5 interact physically, and the activation of GATA4, in cooperation with NKX2-5, is essential for stretch-induced cardiomyocyte hypertrophy. Here, we report the identification of four small molecule families that either inhibit or enhance the GATA4-NKX2-5 transcriptional synergy. A fragment-based screening, reporter gene assay, and pharmacophore search were utilized for the small molecule screening, identification, and optimization. The compounds modulated the hypertrophic agonist-induced cardiac gene expression. The most potent hit compound, N-[4-(diethylamino)phenyl]-5-methyl-3-phenylisoxazole-4-carboxamide (3, IC50 = 3 mu M), exhibited no activity on the protein kinases involved in the regulation of GATA4 phosphorylation. The identified and chemically and biologically characterized active compound, and its derivatives may provide a novel class of small molecules for modulating heart regeneration.
  • Jarvinen, Erkka; Sjöstedt, Noora; Koenderink, Jan B.; Kidron, Heidi; Finel, Moshe (2019)
    Nicotine is the addiction causing alkaloid in tobacco, and it is used in smoking cessation therapies. Although the metabolic pathways of nicotine are well known and mainly occur in the liver, the transport of nicotine and its metabolites is poorly characterized. The highly hydrophilic nature and urinary excretion of nicotine glucuronide metabolites indicate that hepatic basolateral efflux transporters mediate their excretion. We aimed here to find the transporters responsible for the hepatic excretion of nicotine, cotinine and trans-3 '-hydroxycotinine (OH-cotinine) glucuronides. To this end, we tested their transport by multidrug resistance-associated proteins 1 (MRP1, ABCC1) and MRP3-6 (ABCC3-6), which are located on the basolateral membranes of hepatocytes, as well as MRP2 (ABCC2), breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance protein 1 (MDR1, P-gp, ABCB1) that are expressed in the apical membranes of these cells. ATP-dependent transport of these glucuronides was evaluated in inside-out membrane vesicles expressing the transporter of interest. In addition, potential interactions of both the glucuronides and parent compounds with selected transporters were tested by inhibition assays. Considerable ATP-dependent transport was observed only for OH-cotinine glucuronide by MRP3. The kinetics of this transport activity was characterized, resulting in an estimated K-m value of 895 mu mol/L. No significant transport was found for nicotine or cotinine glucuronides by any of the tested transporters at either 5 or 50 mu mol/L substrate concentration. Furthermore, neither nicotine, cotinine nor OH-cotinine inhibited MRP2-4, BCRP or MDR1. In this study, we directly examined, for the first time, efflux transport of the three hydrophilic nicotine glucuronide metabolites by the major human hepatic efflux transporters. Despite multiple transporters studied here, our results indicate that an unknown transporter may be responsible for the hepatic excretion of nicotine and cotinine glucuronides.
  • Skok, Žiga; Barančoková, Michaela; Benek, Ondřej; Cruz, Cristina Durante; Tammela, Päivi; Tomašič, Tihomir; Zidar, Nace; Mašič, Lucija Peterlin; Zega, Anamarija; Stevenson, Clare E. M.; Mundy, Julia E. A.; Lawson, David M.; Maxwell, Anthony; Kikelj, Danijel; Ilaš, Janez (2020)
    We designed and synthesized a series of inhibitors of the bacterial enzymes DNA gyrase and DNA topoisomerase IV, based on our recently published benzothiazole-based inhibitor bearing an oxalyl moiety. To improve the antibacterial activity and retain potent enzymatic activity, we systematically explored the chemical space. Several strategies of modification were followed: varying substituents on the pyrrole carboxamide moiety, alteration of the central scaffold, including variation of substitution position and, most importantly, modification of the oxalyl moiety. Compounds with acidic, basic, and neutral properties were synthesized. To understand the mechanism of action and binding mode, we have obtained a crystal structure of compound 16a, bearing a primary amino group, in complex with the N-terminal domain of E. coli gyrase B (24 kDa) (PDB: 6YD9). Compound 15a, with a low molecular weight of 383 Da, potent inhibitory activity on E. coli gyrase (IC50 = 9.5 nM), potent antibacterial activity on E. faecalis (MIC = 3.13 mu M), and efflux impaired E. coli strain (MIC = 0.78 mu M), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-negative bacteria.
  • Haverinen, Jaakko; Hassinen, Minna; Dash, Surjya Narayan; Vornanen, Matti (2018)
    Calcium channels are necessary for cardiac excitation-contraction (E-C) coupling, but Ca2+ channel composition of fish hearts is still largely unknown. To this end, we determined transcript expression of Ca2+ channels in the heart of zebrafish (Danio rerio), a popular model species. Altogether, 18 Ca2+ channel alpha-subunit genes were expressed in both atrium and ventricle. Transcripts for 7 L-type (Ca(v)1.1a, Ca(v)1.1b, Ca(v)1.2, Ca(v)1.3a, Ca(v)1.3b, Ca(v)1.4a, Ca(v)1.4b), 5 T-type (Ca(v)3.1, Ca(v)3.2a, Ca(v)3.2b, Ca(v)3.3a, Ca(v)3.3b) and 6 P/Q-, N - and R-type (Ca(v)2.1a, Ca(v)2.1b, Ca(v)2.2a, Ca(v)2.2b, Ca(v)2.3a, Ca(v)2.3b) Ca2+ channels were expressed. In the ventricle, T-type channels formed 54.9%, L-type channels 41.1% and P/Q-, N- and R-type channels 4.0% of the Ca2+ channel transcripts. In the atrium, the relative expression of T-type and L-type Ca2+ channel transcripts was 64.1% and 33.8%, respectively (others accounted for 2.1%). Thus, at the transcript level, T-type Ca2+ channels are prevalent in zebrafish atrium and ventricle. At the functional level, peak densities of ventricular T-type (I-CAT) and L-type (I-CAL) Ca2+ current were 6.3 +/- 0.8 and 7.7 +/- 0.8 pA pF(-1), respectively. I-CAT mediated a sizeable sarcolemmal Ca2+ influx into ventricular myocytes: the increment in total cellular Ca2+ content via I-CAT was 41.2 +/- 7.3 mu mol l(-1), which was 31.7% of the combined Ca2+ influx (129 mu mol l(-1)) via I(CAT )and I(CAL)( ()88.5 +/- 20.5 mu mol l(-1)). The diversity of expressed Ca2+ channel genes in zebrafish heart is high, but dominated by the members of the T-type subfamily. The large ventricular I(CAT )is likely to play a significant role in E-C coupling.
  • Wang, Yinyin; Yang, Hongbin; Chen, Linxiao; Jafari, Mohieddin; Tang, Jing (2021)
    Traditional Chinese medicine (TCM) has been practiced for thousands of years for treating human diseases. In comparison to modern medicine, one of the advantages of TCM is the principle of herb compatibility, known as TCM formulae. A TCM formula usually consists of multiple herbs to achieve the maximum treatment effects, where their interactions are believed to elicit the therapeutic effects. Despite being a fundamental component of TCM, the rationale of combining specific herb combinations remains unclear. In this study, we proposed a network-based method to quantify the interactions in herb pairs. We constructed a protein–protein interaction network for a given herb pair by retrieving the associated ingredients and protein targets, and determined multiple network-based distances including the closest, shortest, center, kernel, and separation, both at the ingredient and at the target levels. We found that the frequently used herb pairs tend to have shorter distances compared to random herb pairs, suggesting that a therapeutic herb pair is more likely to affect neighboring proteins in the human interactome. Furthermore, we found that the center distance determined at the ingredient level improves the discrimination of top-frequent herb pairs from random herb pairs, suggesting the rationale of considering the topologically important ingredients for inferring the mechanisms of action of TCM. Taken together, we have provided a network pharmacology framework to quantify the degree of herb interactions, which shall help explore the space of herb combinations more effectively to identify the synergistic compound interactions based on network topology.
  • Zidar, Nace; Macut, Helena; Tomašič, Tihomir; Peterlin Mašič, Lucija; Ilaš, Janez; Zega, Anamarija; Tammela, Päivi; Kikelj, Danijel (2019)
    Due to the rapid development of antimicrobial resistance, the discovery of new antibacterials is essential in the fight against potentially lethal infections. The DNA gyrase B (GyrB) subunit of bacterial DNA gyrase is an excellent target for the design of antibacterials, as it has been clinically validated by novobiocin. However, there are currently no drugs in clinical use that target GyrB. We prepared a new series of N-phenyl-4,5-dibromopyrrolamides and evaluated them against DNA gyrase and against the structurally and functionally similar enzyme, topoisomerase IV. The most active compound, 28, had an IC50 of 20 nM against Escherichia coli DNA gyrase. The IC50 values of 28 against Staphylococcus aureus DNA gyrase, and E. coli and S. aureus topoisomerase IV were in the low micromolar range. However, the compounds evaluated did not show significant antibacterial activities against selected Gram-positive and Gram-negative bacteria. Our results indicate that for potent inhibition of DNA gyrase, a combination of polar groups on the carboxylic end of the molecule and substituents that reach into the 'lipophilic floor' of the enzyme is required.
  • Fallarero , Adyary; Batista-González, Ana; Hiltunen, Anna K.; Liimatainen, Jaana; Karonen, Maarit; Vuorela, Pia M. (2015)
    Natural products are complex matrices of compounds that are prone to interfere with the label-dependent methods that are typically used for cytotoxicity screenings. Here, we developed a label-free Electric Cell-substrate Impedance Sensing (ECIS)-based cytotoxicity assay that can be applied in the assessment of the cytotoxicity of natural extracts. The conditions to measure the impedance using ECIS were first optimized in mice immortalized hypothalamic neurons GT1-7 cells. The performance of four natural extracts when tested using three conventional cytotoxicity assays in GT1-7 cells, was studied. Betula pendula (silver birch tree) was found to interfere with all of the cytotoxicity assays in which labels were applied. The silver birch extract was also proven to be cytotoxic and, thus, served as a proof-of-concept for the use of ECIS. The extract was fractionated and the ECIS method permitted the distinction of specific kinetic patterns of cytotoxicity on the fractions as well as the extract's pure constituents. This study offers evidence that ECIS is an excellent tool for real-time monitoring of the cytotoxicity of complex extracts that are difficult to work with using conventional (label-based) assays. Altogether, it offers a very suitable cytotoxicity-screening assay making the work with natural products less challenging within the drug discovery workflow.
  • Parkkila, Petteri; Viitala, Tapani (2020)
    We have utilized multiparametric surface plasmon resonance and impendance-based quartz crystal microbalance instruments to study the distribution coefficients of catechol derivatives in cell model membranes. Our findings verify that the octanol-water partitioning coefficient is a poor descriptor of the total lipid affinity for small molecules which show limited lipophilicity in the octanol-water system. Notably, 3-methoxytyramine, the methylated derivative of the neurotransmitter dopamine, showed substantial affinity to the lipids despite its nonlipophilic nature predicted by octanol-water partitioning. The average ratio of distribution coefficients between 3-methoxytyramine and dopamine was 8.0. We also found that the interactions between the catechols and the membranes modeling the cell membrane outer leaflet are very weak, suggesting a mechanism other than the membrane-mediated mechanism of action for the neurotransmitters at the postsynaptic site. The average distribution coefficient for these membranes was one-third of the average value for pure phosphatidylcholine membranes, calculated using all compounds. In the context of our previous work, we further theorize that membrane-bound enzymes can utilize membrane headgroup partitioning to find their substrates. This could explain the differences in enzyme affinity between soluble and membrane-bound isoforms of catechol-O-methyltransferase, an essential enzyme in catechol metabolism.
  • Wan, Xing; Hendrix, Hanne; Skurnik, Mikael; Lavigne, Rob (2021)
    The deeply intertwined evolutionary history between bacteriophages and bacteria has endowed phages with highly specific mechanisms to hijack bacterial cell metabolism for their propagation. Here, we present a comprehensive, phage-driven strategy to reveal novel antibacterial targets by the exploitation of phage-bacteria interactions. This strategy will enable the design of small molecules, which mimic the inhibitory phage proteins, and allow the subsequent hit-to-lead development of these antimicrobial compounds. This proposed small molecule approach is distinct from phage therapy and phage enzyme-based antimicrobials and may produce a more sustainable generation of new antibiotics that exploit novel bacterial targets and act in a pathogen-specific manner.
  • Bromann, Paul Andrew; Korkaya, Hasan; Webb, Craig P.; Miller, Jeremy; Calvin, Tammy L.; Courtneidge, Sara A. (2005)
    The Src family of protein-tyrosine kinases (SFKs) participates in a variety of signal transduction pathways, including promotion of cell growth, prevention of apoptosis, and regulation of cell interactions and motility. In particular, SFKs are required for the mitogenic response to platelet-derived growth factor (PDGF). However, it is not clear whether there is a discrete SFK-specific pathway leading to enhanced gene expression or whether SFKs act to generally enhance PDGF-stimulated gene expression. To examine this, we treated quiescent NIH3T3 cells with PDGF in the presence or absence of small molecule inhibitors of SFKs, phosphatidylinositol 3-kinase (PI3K), and MEK1/2. Global patterns of gene expression were analyzed by using Affymetrix Gene-Chip arrays, and data were validated by using reverse transcription-PCR and ribonuclease protection assay. We identified a discrete set of immediate early genes induced by PDGF and inhibited in the presence of the SFK-selective inhibitor SU6656. A subset of these SFK-dependent genes was induced by PDGF even in the presence of the MEK1/2 inhibitor U0126 or the PI3K inhibitor LY294002. By using ribonuclease protection assays and nuclear run-off assays, we further determined that PDGF did not stimulate the rate of transcription of these SFK-dependent immediate early genes but rather promoted mRNA stabilization. Our data suggest that PDGF regulates gene expression through an SFK-specific pathway that is distinct from the Ras-MAPK and PI3K pathways, and that SFKs signal gene expression by enhancing mRNA stability.
  • Hussein, Hiba Abi; Borrel, Alexandre; Geneix, Colette; Petitjean, Michel; Regad, Leslie; Camproux, Anne-Claude (2015)
    Predicting protein pocket's ability to bind drug-like molecules with high affinity, i.e. druggability, is of major interest in the target identification phase of drug discovery. Therefore, pocket druggability investigations represent a key step of compound clinical progression projects. Currently computational druggability prediction models are attached to one unique pocket estimation method despite pocket estimation uncertainties. In this paper, we propose 'PockDrug-Server' to predict pocket druggability, efficient on both (i) estimated pockets guided by the ligand proximity (extracted by proximity to a ligand from a holo protein structure) and (ii) estimated pockets based solely on protein structure information (based on amino atoms that form the surface of potential binding cavities). PockDrug-Server provides consistent druggability results using different pocket estimation methods. It is robust with respect to pocket boundary and estimation uncertainties, thus efficient using apo pockets that are challenging to estimate. It clearly distinguishes druggable from less druggable pockets using different estimation methods and outperformed recent druggability models for apo pockets. It can be carried out from one or a set of apo/holo proteins using different pocket estimation methods proposed by our web server or from any pocket previously estimated by the user. PockDrug-Server is publicly available at: http://pockdrug.rpbs.univ-paris-diderot.fr.
  • Wang, Yinyin; Jafari, Mohieddin; Tang, Yun; Tang, Jing (2019)
    Plant-derived nature products, known as herb formulas, have been commonly used in Traditional Chinese Medicine (TCM) for disease prevention and treatment. The herbs have been traditionally classified into different categories according to the TCM Organ systems known as Meridians. Despite the increasing knowledge on the active components of the herbs, the rationale of Meridian classification remains poorly understood. In this study, we took a machine learning approach to explore the classification of Meridian. We determined the molecule features for 646 herbs and their active components including structure-based fingerprints and ADME properties (absorption, distribution, metabolism and excretion), and found that the Meridian can be predicted by machine learning approaches with a top accuracy of 0.83. We also identified the top compound features that were important for the Meridian prediction. To the best of our knowledge, this is the first time that molecular properties of the herb compounds are associated with the TCM Meridians. Taken together, the machine learning approach may provide novel insights for the understanding of molecular evidence of Meridians in TCM. Author summary In East Asia, plant-derived natural products, known as herb formulas, have been commonly used as Traditional Chinese Medicine (TCM) for disease prevention and treatment. According to the theory of TCM, herbs can be classified as different Meridians according to the balance of Yin and Yang, which are commonly understood as metaphysical concepts. Therefore, the scientific rational of Meridian classification remains poorly understood. The aim of our study was to provide a computational means to understand the classification of Meridians. We showed that the Meridians of herbs can be predicted by the molecular and chemical features of the ingredient compounds, suggesting that the Meridians indeed are associated with the properties of the compounds. Our work provided a novel chemoinformatics approach which may lead to a more systematic strategy to identify the mechanisms of action and active compounds for TCM herbs.
  • Subramanian, Vigneshwari; Prusis, Peteris; Xhaard, Henri; Wohlfahrt, Gerd (2016)
    Proteochemometrics, a method that simultaneously uses protein and ligand description, was used to model the target-ligand interaction space of 95 kinases and 1572 inhibitors. To build models, we applied 3-dimensional field-based description of the receptors, which allows the visualization of receptor and ligand features relevant for activity within the spatial framework of the binding sites. Receptor fields were derived from knowledge-based potentials and Schrodinger's WaterMaps, while ligands were described by different 1D, 2D and 3D descriptors. Besides good interpretability, which is important for inhibitor design, the obtained proteochemometric models also predicted external test sets with active and inactive ligands or additional protein targets for ligands with more than 80% accuracy and AUCs above 0.8.
  • Fontana, Flavia; Figueiredo, Patricia; Martins, João Pedro; Santos, Hélder A. (2021)
    In vivo models remain a principle screening tool in the drug discovery pipeline. Here, the challenges associated with the need for animal experiments, as well as their impact on research, individual/societal, and economic contexts are discussed. A number of alternatives that, with further development, optimization, and investment, may replace animal experiments are also revised.
  • Kibble, Milla; Khan, Suleiman A.; Saarinen, Niina; Iorio, Francesco; Saez-Rodriguez, Julio; Makela, Sari; Aittokallio, Tero (2016)
    Drug discovery is moving away from the single target-based approach towards harnessing the potential of polypharmacological agents that modulate the activity of multiple nodes in the complex networks of deregulations underlying disease phenotypes. Computational network pharmacology methods that use systems-level drug-response phenotypes, such as those originating from genome-wide transcriptomic profiles, have proved particularly effective for elucidating the mechanisms of action of multitargeted compounds. Here, we show, via the case study of the natural product pinosylvin, how the combination of two complementary network-based methods can provide novel, unexpected mechanistic insights. This case study also illustrates that elucidating the mechanism of action of multitargeted natural products through transcriptional response-based approaches is a challenging endeavor, often requiring multiple computational-experimental iterations.
  • Serra, Angela; Fratello, Michele; Cattelani, Luca; Liampa, Irene; Melagraki, Georgia; Kohonen, Pekka; Nymark, Penny; Federico, Antonio; Kinaret, Pia Anneli Sofia; Jagiello, Karolina; Ha, My Kieu; Choi, Jang-Sik; Sanabria, Natasha; Gulumian, Mary; Puzyn, Tomasz; Yoon, Tae-Hyun; Sarimveis, Haralambos; Grafström, Roland; Afantitis, Antreas; Greco, Dario (2020)
    Transcriptomics data are relevant to address a number of challenges in Toxicogenomics (TGx). After careful planning of exposure conditions and data preprocessing, the TGx data can be used in predictive toxicology, where more advanced modelling techniques are applied. The large volume of molecular profiles produced by omics-based technologies allows the development and application of artificial intelligence (AI) methods in TGx. Indeed, the publicly available omics datasets are constantly increasing together with a plethora of different methods that are made available to facilitate their analysis, interpretation and the generation of accurate and stable predictive models. In this review, we present the state-of-the-art of data modelling applied to transcriptomics data in TGx. We show how the benchmark dose (BMD) analysis can be applied to TGx data. We review read across and adverse outcome pathways (AOP) modelling methodologies. We discuss how network-based approaches can be successfully employed to clarify the mechanism of action (MOA) or specific biomarkers of exposure. We also describe the main AI methodologies applied to TGx data to create predictive classification and regression models and we address current challenges. Finally, we present a short description of deep learning (DL) and data integration methodologies applied in these contexts. Modelling of TGx data represents a valuable tool for more accurate chemical safety assessment. This review is the third part of a three-article series on Transcriptomics in Toxicogenomics.