@article{ShityakovSkorbFoersteretal.2021,
  author    = {Shityakov, Sergey and Skorb, Ekaterina V. and F{\"o}rster, Carola Y. and Dandekar, Thomas},
  title     = {Scaffold Searching of FDA and EMA-Approved Drugs Identifies Lead Candidates for Drug Repurposing in Alzheimer's Disease},
  series = {Frontiers in Chemistry},
  volume    = {9},
  journal   = {Frontiers in Chemistry},
  issn      = {2296-2646},
  doi       = {10.3389/fchem.2021.736509},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248703},
  year      = {2021},
  abstract  = {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.},
  language  = {en}
}
@article{LiangBencurovaPsotaetal.2021,
  author    = {Liang, Chunguang and Bencurova, Elena and Psota, Eric and Neurgaonkar, Priya and Prelog, Martina and Scheller, Carsten and Dandekar, Thomas},
  title     = {Population-predicted MHC class II epitope presentation of SARS-CoV-2 structural proteins correlates to the case fatality rates of COVID-19 in different countries},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {5},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22052630},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258936},
  year      = {2021},
  abstract  = {We observed substantial differences in predicted Major Histocompatibility Complex II (MHCII) epitope presentation of SARS-CoV-2 proteins for different populations but only minor differences in predicted MHCI epitope presentation. A comparison of this predicted epitope MHC-coverage revealed for the early phase of infection spread (till day 15 after reaching 128 observed infection cases) highly significant negative correlations with the case fatality rate. Specifically, this was observed in different populations for MHC class II presentation of the viral spike protein (p-value: 0.0733 for linear regression), the envelope protein (p-value: 0.023), and the membrane protein (p-value: 0.00053), indicating that the high case fatality rates of COVID-19 observed in some countries seem to be related with poor MHC class II presentation and hence weak adaptive immune response against these viral envelope proteins. Our results highlight the general importance of the SARS-CoV-2 structural proteins in immunological control in early infection spread looking at a global census in various countries and taking case fatality rate into account. Other factors such as health system and control measures become more important after the early spread. Our study should encourage further studies on MHCII alleles as potential risk factors in COVID-19 including assessment of local populations and specific allele distributions.},
  language  = {en}
}
@article{OthmanFathyBekhitetal.2021,
  author    = {Othman, Eman M. and Fathy, Moustafa and Bekhit, Amany Abdlrehim and Abdel-Razik, Abdel-Razik H. and Jamal, Arshad and Nazzal, Yousef and Shams, Shabana and Dandekar, Thomas and Naseem, Muhammad},
  title     = {Modulatory and toxicological perspectives on the effects of the small molecule kinetin},
  series = {Molecules},
  volume    = {26},
  journal   = {Molecules},
  number    = {3},
  issn      = {1420-3049},
  doi       = {10.3390/molecules26030670},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223064},
  year      = {2021},
  abstract  = {Plant hormones are small regulatory molecules that exert pharmacological actions in mammalian cells such as anti-oxidative and pro-metabolic effects. Kinetin belongs to the group of plant hormones cytokinin and has been associated with modulatory functions in mammalian cells. The mammalian adenosine receptor (A2a-R) is known to modulate multiple physiological responses in animal cells. Here, we describe that kinetin binds to the adenosine receptor (A2a-R) through the Asn253 residue in an adenosine dependent manner. To harness the beneficial effects of kinetin for future human use, we assess its acute toxicity by analyzing different biochemical and histological markers in rats. Kinetin at a dose below 1 mg/kg had no adverse effects on the serum level of glucose or on the activity of serum alanine transaminase (ALT) or aspartate aminotransferase (AST) enzymes in the kinetin treated rats. Whereas, creatinine levels increased after a kinetin treatment at a dose of 0.5 mg/kg. Furthermore, 5 mg/kg treated kinetin rats showed normal renal corpuscles, but a mild degeneration was observed in the renal glomeruli and renal tubules, as well as few degenerated hepatocytes were also observed in the liver. Kinetin doses below 5 mg/kg did not show any localized toxicity in the liver and kidney tissues. In addition to unraveling the binding interaction between kinetin and A2a-R, our findings suggest safe dose limits for the future use of kinetin as a therapeutic and modulatory agent against various pathophysiological conditions.},
  language  = {en}
}
@article{AudretschGrataniWolzetal.2021,
  author    = {Audretsch, Christof and Gratani, Fabio and Wolz, Christiane and Dandekar, Thomas},
  title     = {Modeling of stringent-response reflects nutrient stress induced growth impairment and essential amino acids in different Staphylococcus aureus mutants},
  series = {Scientific Reports},
  volume    = {11},
  journal   = {Scientific Reports},
  number    = {1},
  doi       = {10.1038/s41598-021-88646-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260313},
  year      = {2021},
  abstract  = {Stapylococcus aureus colonises the nose of healthy individuals but can also cause a wide range of infections. Amino acid (AA) synthesis and their availability is crucial to adapt to conditions encountered in vivo. Most S. aureus genomes comprise all genes required for AA biosynthesis. Nevertheless, different strains require specific sets of AAs for growth. In this study we show that regulation inactivates pathways under certain conditions which result in these observed auxotrophies. We analyzed in vitro and modeled in silico in a Boolean semiquantitative model (195 nodes, 320 edges) the regulatory impact of stringent response (SR) on AA requirement in S. aureus HG001 (wild-type) and in mutant strains lacking the metabolic regulators RSH, CodY and CcpA, respectively. Growth in medium lacking single AAs was analyzed. Results correlated qualitatively to the in silico predictions of the final model in 92\% and quantitatively in 81\%. Remaining gaps in our knowledge are evaluated and discussed. This in silico model is made fully available and explains how integration of different inputs is achieved in SR and AA metabolism of S. aureus. The in vitro data and in silico modeling stress the role of SR and central regulators such as CodY for AA metabolisms in S. aureus.},
  language  = {en}
}