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Artocarpus altilis CG-901 alters critical nodes in the JH1-kinase domain of Janus kinase 2 affecting upstream JAK/STAT3 signaling

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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.

Upper panel Janus kinase 2 upstream signaling pathway. Lower panel Apo-JAK2 (left) and CG-901-bound JAK2 (right)

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Acknowledgment

This work was partly supported by the H3Africa Bioinformatics Network (H3ABioNet) grant funded by NIH Common Fund Award/NHGRI (Grant Number U41HG006941).

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Authors and Affiliations

  1. Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja, Nigeria

    Oyekanmi Nash & Lucy Ogbadu

  2. Center for Biocomputing, Adekunle Ajasin University, Akungba-Akoko, Nigeria

    Olaposi Omotuyi

  3. Department of Pharmacology and Therapeutic Innovation, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan

    Olaposi Omotuyi

  4. International Biological Material Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea

    Joonku Lee

  5. Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon, Republic of Korea

    Byoung-Mog Kwon

  6. Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Nigeria

    Oyekanmi Nash

  7. H3Africa Bioinformatics Network Node, National Biotechnology Development Agency (NABDA), Abuja, Nigeria

    Oyekanmi Nash & Olaposi Omotuyi

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  1. Oyekanmi Nash
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Correspondence to Olaposi Omotuyi.

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Supplementary Fig. S1

Binding signature and dynamics of JAK3-JH1 CG-901 or 3QX bound states. a Free energy surface plots of Apo-JAK3 (I), JAK3-QUP (ii), and JAK3-CG-901 complex. b Upper plane) Representative low-energy conformation of 3QX (red stick)-JAK3 (blue cartoon) complex, green stick JAK3 residues interacting with 3QX (cyan stick). Lower plane) Representative low-energy conformation of CG-901 (green stick)-JAK3 (blue cartoon) complex; cyan stick represents the JAK3 residues interacting with CG-901 (green stick). c Line plots of χ1 (I, upper plane) and χ2 (I, lower plane) dihedral angle distribution of Tyr1007 along the trajectory, (ii upper plane) root mean square deviation of the nucleotide binding loop, (ii lower plane) catalytic loop, (iii, upper plane) activation loop during the trajectories. (iii, lower plane) center of mass distance between tyrosine 1007 and aspartate 1004 during the course of the simulation. d Cartoon representation of apo-JAK3 (I), 3QX-bound (ii), and CG-901-bound (iii) JAK3. Blue spheres and line (thickness represents weight) represent critical network. Lines plot are color coded: Red Apo-protein, Blue lines 3QX-bound JAK3, green lines represent CG-901-bound JAK3. (PDF 5.70 mb)

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Nash, O., Omotuyi, O., Lee, J. et al. Artocarpus altilis CG-901 alters critical nodes in the JH1-kinase domain of Janus kinase 2 affecting upstream JAK/STAT3 signaling. J Mol Model 21, 280 (2015). https://doi.org/10.1007/s00894-015-2821-z

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