Repurposing Biomolecules from Aerva javanica Against DDX3X in LAML: A Computer-Aided Therapeutic Approach

Abstract

Acute Myeloid Leukemia (LAML) is a life-threatening hematological malignancy, and the DEAD-box helicase 3 X-linked (DDX3X) gene is a potential yet underexplored target gene for LAML. Biomolecules derived from medicinal plants like Aerva javanica offer a great source of therapeutic candidates. This study aimed to investigate the role of DDX3X in LAML and identify plant-derived biomolecules that could inhibit DDX3X using computational approaches. Pan-cancer mutational profiling, a transcriptomic analysis, survival, protein-protein interaction networks, and a principal component analysis (PCA) were employed to elucidate functional associations and transcriptomic divergence. Subsequently, biomolecules from A. javanica were subjected to in silico screening using molecular docking and ADMET profiling. The docking protocol was validated using RK-33, a known DDX3X inhibitor. DDX3X was found to be linked to key leukemogenic pathways, including Wnt/β-catenin and MAPK signaling, indicating it to be a potential target. Molecular docking of A. javanica compounds revealed CIDs 15559724, 5490003, and 74819331 as potent DDX3X inhibitors with strong binding affinity and favorable pharmacokinetic and toxicity profiles compared to RK-33. This study highlights the importance of DDX3X in LAML pathogenesis and suggests targeting it using plant-derived inhibitors, which may require further in vitro and in vivo validation.

Keywords: A. javanica; ADMET; DEAD-box helicase 3 X-linked (DDX3X); acute myeloid leukemia (LAML); molecular docking.

Figure 1

The distribution of the most frequently mutated genes in Acute Myeloid Leukemia (LAML). The bar graph illustrates the percentage of LAML cases affected by mutations in the top mutated genes based on TCGA data. The gene B2M exhibits the highest mutation frequency (>13%), followed by DEAD-box helicase 3 X-linked (DDX3X), human epidermal growth factor receptor 3 (ERBB3), breast cancer gene 1 (BRCA1), and ASXL Transcriptional Regulator 2 (ASXL2), with each affecting 4–8% of cases.

Figure 2

The pan-cancer expression profile of DDX3X was analyzed across TCGA tumor datasets, comparing the transcript levels (TPM) between tumor (red) and normal (green) tissues for various cancer types using GEPIA 2 data. Each dot indicates the individual sample expression, with the black lines showing the median expression levels.

Figure 3

The expression analysis of DDX3X in Acute Myeloid Leukemia (LAML). (A) The DDX3X expression across different LAML subtypes (M0–M7) based on the French–American–British (FAB) classification. (B) The expression in LAML patients grouped by age ranges (21–100 years). (C) The expression among LAML patients from different racial backgrounds. Transcript levels are measured in Transcripts Per Million (TPM). Box plots show the medians, interquartile ranges, and overall distribution.

Figure 4

The survival analysis of the DDX3X expression in patients with LAML. (A) The Kaplan–Meier curve for the overall survival (OS) comparing patients with high and low DDX3X expression levels. The p-value of 0.94, with a hazard ratio (HR) of 1.0, indicates no significant difference in the OS between groups. (B) The disease-free survival (DFS) analysis also demonstrated no difference between the high- and low-DDX3X-expression groups.

Figure 5

The principal component analysis (PCA) plot of genes positively correlated with DDX3X in LAML. The PCA was performed to assess the expression pattern of DDX3X-correlated genes in LAML tumor samples (red) versus whole blood controls (brown), indicating distinct variance in LAML vs. whole blood controls.

Figure 6

The DDX3X protein network. Proteins with a strong positive correlation with DDX3X in LAML are clustered into three categories based on k-means clustering in the STRING software v.12.0.

Figure 7

Docking and intra-molecular interactions. (A) All of the superimposed A. javanica compounds (as stick representations) docked into the binding pocket of DDX3X (ODB ID: 2I4I_A) (as cartoon representations), with the top compounds from A. javanica shown in 3D to show the binding surface of the receptor and in 2D representation to show the intra-molecular interactions and their distances in Å. Green dashes represent hydrogen bonds, pink dashes represent hydrophobic interactions, and orange dashes represent electrostatic interactions. Docked compounds: CID 15559724, (B) 3D and (C) 2D; CID 5490003, (D) 3D and (E) 2D; CID 74819331, (F) 3D and (G) 2D.

Figure 7

Docking and intra-molecular interactions. (A) All of the superimposed A. javanica compounds (as stick representations) docked into the binding pocket of DDX3X (ODB ID: 2I4I_A) (as cartoon representations), with the top compounds from A. javanica shown in 3D to show the binding surface of the receptor and in 2D representation to show the intra-molecular interactions and their distances in Å. Green dashes represent hydrogen bonds, pink dashes represent hydrophobic interactions, and orange dashes represent electrostatic interactions. Docked compounds: CID 15559724, (B) 3D and (C) 2D; CID 5490003, (D) 3D and (E) 2D; CID 74819331, (F) 3D and (G) 2D.