Potential JAK2 Inhibitors from Selected Natural Compounds: A Promising Approach for Complementary Therapy in Cancer Patients

Abstract

Background: Janus-activated kinase 2 (JAK2) plays a pivotal role in numerous essential biological processes, including proliferation, apoptosis, and metastasis in human cells. Prior studies have indicated that inhibiting JAK2 could be a promising strategy to mitigate cell proliferation and induce apoptosis in tumor cells.

Objectives: This study aimed to estimate the binding affinity of 79 herbal compounds, comprising 46 flavonoids, 21 anthraquinones, and 12 cinnamic acids, to the ATP-binding cleft of JAK2 to identify potential herbal inhibitors of JAK2.

Methods: The binding affinities between ligands and JAK2 were calculated utilizing AutoDock 4.0 software in conjunction with the Cygwin environment. Cross-validation was conducted using the Schrödinger tool. Molecular dynamics simulations were employed to evaluate the stability of docked poses for the most significant JAK2 inhibitors. Furthermore, the Discovery Studio Visualizer tool was utilized to elucidate interactions between the top-ranked JAK2 inhibitors and residues within the JAK2 ATP-binding site.

Results: Twelve flavonoids, two anthraquinones, and three cinnamic acids demonstrated substantial binding affinities to the protein kinase domain of the receptor, with a criterion of ΔG_binding < -10 kcal/mol. Among the studied flavonoids, anthraquinones, and cinnamic acid derivatives, orientin, chlorogenic acid, and pulmatin emerged as the most potent JAK2 inhibitors, exhibiting ΔG_binding scores of -14.49, -11.87, and -10.76 kcal/mol, respectively. Furthermore, the docked poses of orientin, pulmatin, and chlorogenic acid remained stable throughout 60 ns computer simulations. The average root mean square deviation values calculated for JAK2 when complexed with orientin, chlorogenic acid, and pulmatin were 2.04 Å, 2.06 Å, and 1.95 Å, respectively.

Conclusion: This study underscores the robust inhibitory potential of orientin, pulmatin, and chlorogenic acid against JAK2. The findings hold promise for the development of novel and effective drugs for cancer treatment.

Figure 1

An illustrative depiction portraying the operational mechanism of JAK2 across various pathways linked to the initiation and progression of cancer. JAK2, janus-activated kinase 2.

Figure 2

Lead scaffolds of (a) flavonoids, (b) cinnamic acids, and (c) anthraquinones.

Figure 3

ΔG_binding values between top-ranked herbal compounds, a positive control inhibitor, and JAK2 ATP-binding site. The X-axis shows the compounds' names, and the Y-axis demonstrates the gibbs free binding energy in kcal/mol units. Green, blue, red, and black spots present flavonoids, anthraquinones, cinnamic acids, and a positive control inhibitor. JAK2, janus-activated kinase 2.

Figure 4

RMSD for JAK2 backbone atoms complexed with top-ranked flavonoid, anthraquinone, cinnamic acid derivative, and a positive control inhibitor. The X-axis presents the simulation time, and the Y-axis demonstrates the RMSD. JAK2, janus-activated kinase 2.; RMSD, root-mean-square deviations.

Figure 5

RMSF for JAK2 backbone atoms complexed with 1ZA, orientin, pulmatin, and chlorogenic acid. Pink and yellow regions demonstrate α-helix and β-strand secondary structures from the RCSB databank. The X-axis illustrates the name and number of residues, while the Y-axis shows the RMSF. JAK2, janus-activated kinase 2; RMSF, root mean square fluctuation.

Figure 6

Superimposed structures of JAK2 before and after MD simulations. Cyan and purple colors display the JAK2 before and after MD simulations. Green, blue, red, and black colors present orientin, pulmatin, chlorogenic acid, and 1ZA after 60 ns MD simulations. JAK2, janus-activated kinase 2; MD, molecular dynamics.

Figure 7

Interaction types between orientin (green), pulmatin (blue), chlorogenic acid (red), 1ZA (black), and JAK2 ATP-binding site. The (a and b) images show interactions before and after MD simulation, respectively. JAK2, janus-activated kinase 2; MD, molecular dynamics.