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: Oyekanmi Nash, Olaposi Omotuyi, Joonku Lee, Byoung-Mog Kwon, Lucy Ogbadu
• Journal: Journal of molecular modeling (J Mol Model) Vol. 21 Issue 11 Pg. 280 (Nov 2015) ISSN: 0948-5023 [Electronic] Germany
• PMID: 26442513 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chalcones
• STAT3 Transcription Factor
• Janus Kinase 2
• dihydrochalcone

Topics

• Artocarpus (chemistry)
• Chalcones (isolation & purification, metabolism, pharmacology)
• Humans
• Janus Kinase 2 (antagonists & inhibitors, chemistry, metabolism)
• Molecular Dynamics Simulation
• Phosphorylation
• Protein Structure, Tertiary
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)