caa a22 4500 605513821 CHVBK 20210128100702.0 cr unu---uuuuu 210128e20151101xx s 000 0 eng 10.1007/s00894-015-2821-z doi (NATIONALLICENCE)springer-10.1007/s00894-015-2821-z Artocarpus altilis CG-901 alters critical nodes in the JH1-kinase domain of Janus kinase 2 affecting upstream JAK/STAT3 signaling [Elektronische Daten] [Oyekanmi Nash, Olaposi Omotuyi, Joonku Lee, Byoung-Mog Kwon, Lucy Ogbadu] As a key step in achieving low-cost, easily accessible anti-cancer therapy for low- and middle-income countries, we recently established the scientific basis for the folkloric use of Artocarpus altilis for the treatment of cancer by investigating the geranyl dihydrochalcone (CG-901) content and its interference with signal transducer and activator of transcription 3 (STAT3) phosphorylation and blockage of further downstream signaling. In the current study, the CG-901 upstream target was queried by chemical fingerprinting similarity assessment, semi-empirical (PM6ESCF) QMMM and molecular dynamics (MD) simulation. Moderate (∼0.4) to high (∼0.7) Tanimoto scores were found when the CG-901 scaffold was compared to ligands co-crystallized with Janus kinases (JAK) 1-3. High negative energy values were obtained when the CG-901 was treated semi-empirically (PM6ESCF) within the classical field of JAK (1-3). Multiple nanosecond MD simulations showed that CG-901 did not cause any large structural perturbations in the nucleotide-binding, activation and catalytic loops within the kinase (JH1) domain of JAK (1-3); however, it reduced the energy required to attain metastability along the path to energy minima conformation. In comparison to JAK1 and Apo-state JAK2, JAK2-bound CG-901 exhibited a highly re-organized key intra-domain protein network; indicating atomic level interference with inter-residue communication. In conclusion, CG-901 isolated from A. altilis represents a broad-spectrum JAK inhibitor, which may underlie the mechanism of STAT3 phosphorylation blockage. Graphical abstract Upper panel Janus kinase 2 upstream signaling pathway. Lower panel Apo-JAK2 (left) and CG-901-bound JAK2 (right) Springer-Verlag Berlin Heidelberg, 2015 Artocarpus altilis nationallicence Anticancer nationallicence STAT3 nationallicence Janus kinase nationallicence Geranyl dihydrochalcone nationallicence Critical nodes nationallicence Nash Oyekanmi Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja, Nigeria aut Omotuyi Olaposi Center for Biocomputing, Adekunle Ajasin University, Akungba-Akoko, Nigeria aut Lee Joonku International Biological Material Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea aut Kwon Byoung-Mog Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon, Republic of Korea aut Ogbadu Lucy Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja, Nigeria aut Journal of Molecular Modeling Springer Berlin Heidelberg 21/11(2015-11-01), 1-11 1610-2940 21:11<1 2015 21 894 https://doi.org/10.1007/s00894-015-2821-z text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00894-015-2821-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Nash Oyekanmi Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja, Nigeria aut NATIONALLICENCE 700 1- Omotuyi Olaposi Center for Biocomputing, Adekunle Ajasin University, Akungba-Akoko, Nigeria aut NATIONALLICENCE 700 1- Lee Joonku International Biological Material Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea aut NATIONALLICENCE 700 1- Kwon Byoung-Mog Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon, Republic of Korea aut NATIONALLICENCE 700 1- Ogbadu Lucy Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja, Nigeria aut NATIONALLICENCE 773 0- Journal of Molecular Modeling Springer Berlin Heidelberg 21/11(2015-11-01), 1-11 1610-2940 21:11<1 2015 21 894