TY - JOUR A1 - Shityakov, Sergey A1 - Skorb, Ekaterina V. A1 - Förster, Carola Y. A1 - Dandekar, Thomas T1 - Scaffold Searching of FDA and EMA-Approved Drugs Identifies Lead Candidates for Drug Repurposing in Alzheimer’s Disease JF - Frontiers in Chemistry N2 - Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have consumed a significant amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA), or Worldwide for another indication is a more rapid and less expensive option. Therefore, we apply the scaffold searching approach based on known amyloid-beta (Aβ) inhibitor tramiprosate to screen the DrugCentral database (n = 4,642) of clinically tested drugs. As a result, menadione bisulfite and camphotamide substances with protrombogenic and neurostimulation/cardioprotection effects were identified as promising Aβ inhibitors with an improved binding affinity (ΔGbind) and blood-brain barrier permeation (logBB). Finally, the data was also confirmed by molecular dynamics simulations using implicit solvation, in particular as Molecular Mechanics Generalized Born Surface Area (MM-GBSA) model. Overall, the proposed in silico pipeline can be implemented through the early stage rational drug design to nominate some lead candidates for AD, which will be further validated in vitro and in vivo, and, finally, in a clinical trial. KW - scaffold search KW - approved drugs KW - drug repurposing KW - alzheimer's disease KW - chemical similarity KW - molecular modeling Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248703 SN - 2296-2646 VL - 9 ER - TY - JOUR A1 - Dandekar, Thomas A1 - Fieselmann, Astrid A1 - Fischer, Eva A1 - Popp, Jasmin A1 - Hensel, Michael A1 - Noster, Janina T1 - Salmonella—how a metabolic generalist adopts an intracellular lifestyle during infection JF - Frontiers in Cellular and Infection Microbiology N2 - The human-pathogenic bacterium Salmonella enterica adjusts and adapts to different environments while attempting colonization. In the course of infection nutrient availabilities change drastically. New techniques, “-omics” data and subsequent integration by systems biology improve our understanding of these changes. We review changes in metabolism focusing on amino acid and carbohydrate metabolism. Furthermore, the adaptation process is associated with the activation of genes of the Salmonella pathogenicity islands (SPIs). Anti-infective strategies have to take these insights into account and include metabolic and other strategies. Salmonella infections will remain a challenge for infection biology. KW - regulation KW - virulence KW - "-omics" KW - metabolism KW - Salmonella-containing vacuole (SCV) Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120686 SN - 2235-2988 VL - 4 IS - 191 ER - TY - JOUR A1 - Dandekar, Thomas A1 - Fieselmann, Astrid A1 - Popp, Jasmin A1 - Hensel, Michael T1 - Salmonella enterica: a surprisingly well-adapted intracellular lifestyle JF - Frontiers in Microbiology N2 - The infectious intracellular lifestyle of Salmonella enterica relies on the adaptation to nutritional conditions within the Salmonella-containing vacuole (SCV) in host cells. We summarize latest results on metabolic requirements for Salmonella during infection. This includes intracellular phenotypes of mutant strains based on metabolic modeling and experimental tests, isotopolog profiling using (13)C-compounds in intracellular Salmonella, and complementation of metabolic defects for attenuated mutant strains towards a comprehensive understanding of the metabolic requirements of the intracellular lifestyle of Salmonella. Helpful for this are also genomic comparisons. We outline further recent studies and which analyses of intracellular phenotypes and improved metabolic simulations were done and comment on technical required steps as well as progress involved in the iterative refinement of metabolic flux models, analyses of mutant phenotypes, and isotopolog analyses. Salmonella lifestyle is well-adapted to the SCV and its specific metabolic requirements. Salmonella metabolism adapts rapidly to SCV conditions, the metabolic generalist Salmonella is quite successful in host infection. KW - Salmonella enterica KW - metabolism KW - Salmonella-containing vacuole KW - regulation KW - virulence Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123135 ER - TY - JOUR A1 - Dandekar, Thomas A1 - Fieselmann, Astrid A1 - Fischer, Eva A1 - Popp, Jasmin A1 - Hensel, Michael A1 - Noster, Janina T1 - Salmonella - how a metabolic generalist adopts an intracellular lifestyle during infection JF - Frontiers in Cellular and Infection Microbiology N2 - The human-pathogenic bacterium Salmonella enterica adjusts and adapts to different environments while attempting colonization. In the course of infection nutrient availabilities change drastically. New techniques, "-omics" data and subsequent integration by systems biology improve our understanding of these changes. We review changes in metabolism focusing on amino acid and carbohydrate metabolism. Furthermore, the adaptation process is associated with the activation of genes of the Salmonella pathogenicity islands (SPIs). Anti-infective strategies have to take these insights into account and include metabolic and other strategies. Salmonella infections will remain a challenge for infection biology. KW - enterica serovar Typhimurium KW - bacterial invasion KW - mouse model KW - defenses KW - regulation KW - "-omics" KW - virulence KW - Salmonella-containing vacuole (SCV) KW - metabolism KW - nitric oxide Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149029 VL - 4 IS - 191 ER - TY - JOUR A1 - Gupta, Shishir K. A1 - Minocha, Rashmi A1 - Thapa, Prithivi Jung A1 - Srivastava, Mugdha A1 - Dandekar, Thomas T1 - Role of the pangolin in origin of SARS-CoV-2: an evolutionary perspective JF - International Journal of Molecular Sciences N2 - After the recent emergence of SARS-CoV-2 infection, unanswered questions remain related to its evolutionary history, path of transmission or divergence and role of recombination. There is emerging evidence on amino acid substitutions occurring in key residues of the receptor-binding domain of the spike glycoprotein in coronavirus isolates from bat and pangolins. In this article, we summarize our current knowledge on the origin of SARS-CoV-2. We also analyze the host ACE2-interacting residues of the receptor-binding domain of spike glycoprotein in SARS-CoV-2 isolates from bats, and compare it to pangolin SARS-CoV-2 isolates collected from Guangdong province (GD Pangolin-CoV) and Guangxi autonomous regions (GX Pangolin-CoV) of South China. Based on our comparative analysis, we support the view that the Guangdong Pangolins are the intermediate hosts that adapted the SARS-CoV-2 and represented a significant evolutionary link in the path of transmission of SARS-CoV-2 virus. We also discuss the role of intermediate hosts in the origin of Omicron. KW - COVID-19 KW - SARS-CoV-2 KW - origin KW - evolution KW - intermediate host KW - pangolin KW - mutation KW - recombination KW - adaptation KW - transmission KW - comparative sequence analysis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285995 SN - 1422-0067 VL - 23 IS - 16 ER - TY - JOUR A1 - Sarukhanyan, Edita A1 - Shityakov, Sergey A1 - Dandekar, Thomas T1 - Rational drug design of Axl tyrosine kinase type I inhibitors as promising candidates against cancer JF - Frontiers in Chemistry N2 - The high level of Axl tyrosine kinase expression in various cancer cell lines makes it an attractive target for the development of anti-cancer drugs. In this study, we carried out several sets of in silico screening for the ATP-competitive Axl kinase inhibitors based on different molecular docking protocols. The best drug-like candidates were identified, after parental structure modifications, by their highest affinity to the target protein. We found that our newly designed compound R5, a derivative of the R428 patented analog, is the most promising inhibitor of the Axl kinase according to the three molecular docking algorithms applied in the study. The molecular docking results are in agreement with the molecular dynamics simulations using the MM-PBSA/GBSA implicit solvation models, which confirm the high affinity of R5 toward the protein receptor. Additionally, the selectivity test against other kinases also reveals a high affinity of R5 toward ABL1 and Tyro3 kinases, emphasizing its promising potential for the treatment of malignant tumors. KW - Axl tyrosine kinase KW - anti-cancer drug-like molecules KW - rational drug design KW - molecular docking KW - molecular dynamics Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199505 SN - 2296-2646 VL - 7 IS - 920 ER - TY - INPR A1 - Dandekar, Thomas T1 - Qubit transition into defined Bits: A fresh perspective for cosmology and unifying theories N2 - In this view point we do not change cosmology after the hot fireball starts (hence agrees well with observation), but the changed start suggested and resulting later implications lead to an even better fit with current observations (voids, supercluster and galaxy formation; matter and no antimatter) than the standard model with big bang and inflation: In an eternal ocean of qubits, a cluster of qubits crystallizes to defined bits. The universe does not jump into existence (“big bang”) but rather you have an eternal ocean of qubits in free super-position of all their quantum states (of any dimension, force field and particle type) as permanent basis. The undefined, boiling vacuum is the real “outside”, once you leave our everyday universe. A set of n Qubits in the ocean are “liquid”, in very undefined state, they have all their m possibilities for quantum states in free superposition. However, under certain conditions the qubits interact, become defined, and freeze out, crystals form and give rise to a defined, real world with all possible time series and world lines. GR holds only within the crystal. In our universe all n**m quantum possibilities are nicely separated and crystallized out to defined bit states: A toy example with 6 qubits each having 2 states illustrates, this is completely sufficient to encode space using 3 bits for x,y and z, 1 bit for particle type and 2 bits for its state. Just by crystallization, space, particles and their properties emerge from the ocean of qubits, and following the arrow of entropy, time emerges, following an arrow of time and expansion from one corner of the toy universe to everywhere else. This perspective provides time as emergent feature considering entropy: crystallization of each world line leads to defined world lines over their whole existence, while entropy ensures direction of time and higher representation of high entropy states considering the whole crystal and all slices of world lines. The crystal perspective is also economic compared to the Everett-type multiverse, each qubit has its m quantum states and n qubits interacting forming a crystal and hence turning into defined bit states has only n**m states and not more states. There is no Everett-type world splitting with every decision but rather individual world trajectories reside in individual world layers of the crystal. Finally, bit-separated crystals come and go in the qubit ocean, selecting for the ability to lay seeds for new crystals. This self-organizing reproduction selects over generations also for life-friendliness. Mathematical treatment introduces quantum action theory as a framework for a general lattice field theory extending quantum chromo dynamics where scalar fields for color interaction and gravity have to be derived from the permeating qubit-interaction field. Vacuum energy should get appropriately low by the binding properties of the qubit crystal. Connections to loop quantum gravity, string theory and emergent gravity are discussed. Standard physics (quantum computing; crystallization, solid state physics) allow validation tests of this perspective and will extend current results. KW - qubit KW - cosmology KW - phase transition KW - unified theories KW - crystallization KW - emergent gravity Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266418 ER - TY - INPR A1 - Dandekar, Thomas T1 - Protein folding and crystallization applied to qubit interactions and fundamental physics yields a modified inflation model for cosmology N2 - Protein folding achieves a clear solution structure in a huge parameter space (the so-called protein folding problem). Proteins fold in water, and get by this a highly ordered structure. Finally, inside a protein crystal for structure resolution, you have everywhere the same symmetries as there is everywhere the same unit cell. We apply this to qubit interactions to do fundamental physics: in a modified cosmology, we replace the big bang by a condensation event in an eternal all-encompassing ocean of free qubits. Interactions of qubits in the qubit ocean are quite rare but provide a nucleus or seed for a new universe (domain) as the qubits become decoherent and freeze-out into defined bit ensembles. Second, we replace inflation by a crystallization event triggered by the nucleus of interacting qubits to which rapidly more and more qubits attach (like in everyday crystal growth). The crystal unit cell guarantees same symmetries everywhere inside the crystal. The textbook inflation scenario to explain the same laws of nature in our domain is replaced by the unit cell of the crystal formed. Interacting qubits solidify, quantum entropy decreases (but increases in the ocean around). In a modified inflation scenario, the interacting qubits form a rapidly growing domain where the n**m states become separated ensemble states, rising long-range forces stop ultimately further growth. Then standard cosmology with the hot fireball model takes over. Our theory agrees well with lack of inflation traces in cosmic background measurements. We explain by cosmological crystallization instead of inflation: early creation of large-scale structure of voids and filaments, supercluster formation, galaxy formation, and the dominance of matter: the unit cell of our crystal universe has a matter handedness avoiding anti-matter. We prove initiation of qubit interactions can only be 1,2,4 or 8-dimensional (agrees with E8 symmetry of our universe). Repulsive forces at ultrashort distances result from quantization, long-range forces limit crystal growth. Crystals come and go in the qubit ocean. This selects for the ability to lay seeds for new crystals, for self-organization and life-friendliness. The phase space of the crystal agrees with the standard model of the basic four forces for n quanta. It includes all possible ensemble combinations of their quantum states m, a total of n**m states. Neighbor states reach according to transition possibilities (S-matrix) with emergent time from entropic ensemble gradients. However, in our four dimensions there is only one bit overlap to neighbor states left (almost solid, only below Planck quantum there is liquidity left). The E8 symmetry of heterotic string theory has six curled-up, small dimensions which help to keep the qubit crystal together and will never expand. Mathematics focusses on the Hurwitz proof applied to qubit interaction, a toy model of qubit interaction and repulsive forces of qubits. Vacuum energy gets appropriate low inside the crystal. We give first energy estimates for free qubits vs bound qubits, misplacements in the qubit crystal and entropy increase during qubit decoherence / crystal formation. Scalar fields for color interaction/confinement and gravity are derived from the qubit-interaction field. KW - protein folding KW - crystallization KW - qubit interaction KW - decoherence KW - modified inflation Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-346156 ER - TY - JOUR A1 - Caliskan, Aylin A1 - Crouch, Samantha A. W. A1 - Giddins, Sara A1 - Dandekar, Thomas A1 - Dangwal, Seema T1 - Progeria and aging — Omics based comparative analysis JF - Biomedicines N2 - Since ancient times aging has also been regarded as a disease, and humankind has always strived to extend the natural lifespan. Analyzing the genes involved in aging and disease allows for finding important indicators and biological markers for pathologies and possible therapeutic targets. An example of the use of omics technologies is the research regarding aging and the rare and fatal premature aging syndrome progeria (Hutchinson-Gilford progeria syndrome, HGPS). In our study, we focused on the in silico analysis of differentially expressed genes (DEGs) in progeria and aging, using a publicly available RNA-Seq dataset (GEO dataset GSE113957) and a variety of bioinformatics tools. Despite the GSE113957 RNA-Seq dataset being well-known and frequently analyzed, the RNA-Seq data shared by Fleischer et al. is far from exhausted and reusing and repurposing the data still reveals new insights. By analyzing the literature citing the use of the dataset and subsequently conducting a comparative analysis comparing the RNA-Seq data analyses of different subsets of the dataset (healthy children, nonagenarians and progeria patients), we identified several genes involved in both natural aging and progeria (KRT8, KRT18, ACKR4, CCL2, UCP2, ADAMTS15, ACTN4P1, WNT16, IGFBP2). Further analyzing these genes and the pathways involved indicated their possible roles in aging, suggesting the need for further in vitro and in vivo research. In this paper, we (1) compare “normal aging” (nonagenarians vs. healthy children) and progeria (HGPS patients vs. healthy children), (2) enlist genes possibly involved in both the natural aging process and progeria, including the first mention of IGFBP2 in progeria, (3) predict miRNAs and interactomes for WNT16 (hsa-mir-181a-5p), UCP2 (hsa-mir-26a-5p and hsa-mir-124-3p), and IGFBP2 (hsa-mir-124-3p, hsa-mir-126-3p, and hsa-mir-27b-3p), (4) demonstrate the compatibility of well-established R packages for RNA-Seq analysis for researchers interested but not yet familiar with this kind of analysis, and (5) present comparative proteomics analyses to show an association between our RNA-Seq data analyses and corresponding changes in protein expression. KW - progeria KW - aging KW - omics KW - RNA sequencing KW - bioinformatics KW - sun exposure KW - HGPS KW - IGFBP2 KW - ACKR4 KW - WNT Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-289868 SN - 2227-9059 VL - 10 IS - 10 ER - TY - JOUR A1 - Naseem, Muhammad A1 - Kunz, Meik A1 - Dandekar, Thomas T1 - Probing the unknowns in cytokinin-mediated immune defense in Arabidopsis with systems biology approaches JF - Bioinformatics and Biology Insights N2 - Plant hormones involving salicylic acid (SA), jasmonic acid (JA), ethylene (Et), and auxin, gibberellins, and abscisic acid (ABA) are known to regulate host immune responses. However, plant hormone cytokinin has the potential to modulate defense signaling including SA and JA. It promotes plant pathogen and herbivore resistance; underlying mechanisms are still unknown. Using systems biology approaches, we unravel hub points of immune interaction mediated by cytokinin signaling in Arabidopsis. High-confidence Arabidopsis protein-protein interactions (PPI) are coupled to changes in cytokinin-mediated gene expression. Nodes of the cellular interactome that are enriched in immune functions also reconstitute sub-networks. Topological analyses and their specific immunological relevance lead to the identification of functional hubs in cellular interactome. We discuss our identified immune hubs in light of an emerging model of cytokinin-mediated immune defense against pathogen infection in plants. KW - plant hormones KW - systems biology KW - interaction networks KW - gene expression KW - cytokinin Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120199 SN - 1177-9322 VL - 8 ER -