title: Artocarpus altilis CG-901 alters critical nodes in the JH1-kinase domain of Janus kinase 2 affecting upstream JAK/STAT3 signaling.
abstract: 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).
authors.affiliation: Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja, Nigeria.|Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Nigeria.|H3Africa Bioinformatics Network Node, National Biotechnology Development Agency (NABDA), Abuja, Nigeria.
authors.forename: Oyekanmi
authors.initials: O
authors.lastname: Nash
authors.affiliation: Center for Biocomputing, Adekunle Ajasin University, Akungba-Akoko, Nigeria. omotuyi@nagasaki-u.ac.jp.|Department of Pharmacology and Therapeutic Innovation, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. omotuyi@nagasaki-u.ac.jp.|H3Africa Bioinformatics Network Node, National Biotechnology Development Agency (NABDA), Abuja, Nigeria. omotuyi@nagasaki-u.ac.jp.
authors.forename: Olaposi
authors.initials: O
authors.lastname: Omotuyi
authors.affiliation: International Biological Material Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Joonku
authors.initials: J
authors.lastname: Lee
authors.affiliation: Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Byoung-Mog
authors.initials: BM
authors.lastname: Kwon
authors.affiliation: Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja, Nigeria.
authors.forename: Lucy
authors.initials: L
authors.lastname: Ogbadu
mesh_terms: D031622:Artocarpus / Q000737:chemistry*; D047188:Chalcones / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047188:Chalcones; D050796:STAT3 Transcription Factor; D053614:Janus Kinase 2; C015812:dihydrochalcone
keywords: Anticancer; Artocarpus altilis; Critical nodes; Geranyl dihydrochalcone; Janus kinase; STAT3