The Discovery of Selective Protein Arginine Methyltransferase 5 Inhibitors in the Management of β-Thalassemia through Computational Methods

Abstract

β-Thalassemia is an inherited genetic disorder associated with β-globin chain synthesis, which ultimately becomes anemia. Adenosine-2,3-dialdehyde, by inhibiting arginine methyl transferase 5 (PRMT5), can induce fetal hemoglobin (HbF) levels. Hence, the materialization of PRMT5 inhibitors is considered a promising therapy in the management of β-thalassemia. This study conducted a virtual screening of certain compounds similar to 5'-deoxy-5'methyladenosine (3XV) using the PubChem database. The top 10 compounds were chosen based on the best docking scores, while their interactions with the PRMT5 active site were analyzed. Further, the top two compounds demonstrating the lowest binding energy were subjected to drug-likeness analysis and pharmacokinetic property predictions, followed by molecular dynamics simulation studies. Based on the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) score and molecular interactions, (3R,4S)-2-(6-aminopurin-9-yl)-5-[(4-ethylcyclohexyl)sulfanylmethyl]oxolane-3,4-diol (TOP1) and 2-(6-Aminopurin-9-yl)-5-[(6-aminopurin-9-yl)methylsulfanylmethyl]oxolane-3,4-diol (TOP2) were identified as potential hit compounds, while TOP1 exhibited higher binding affinity and stabler binding capabilities than TOP2 during molecular dynamics simulation (MDS) analysis. Taken together, the outcomes of our study could aid researchers in identifying promising PRMT5 inhibitors. Moreover, further investigations through in vivo and in vitro experiments would unquestionably confirm that this compound could be employed as a therapeutic drug in the management of β-thalassemia.

Keywords: PRMT5 inhibitors; dynamics; fetal hemoglobin; molecular docking; simulations; β-thalassemia.

Figure 1

(A) Suppression of γ-globin gene expression by PRMT5 and its complexes. (B) Reactivation of γ-globin gene expression by inhibiting PRMT5 leads to γ-globin-containing hemoglobin synthesis.

Figure 2

(A) Cartoon representation of crystal structure of PRMT5. (B) Three-dimensional stick representation of PRMT5 active site docked to 3XV ligand. (C) Two-dimensional representation of SAM binding site. (D) Two-dimensional representation of 3XV binding site. (E) Two-dimensional structure of 3XV. (F) Two-dimensional structure of TOP1. (G) Two-dimensional structure of TOP2.

Figure 3

Illustration of PRMT5-docked with different ligands. In (D–F), active site residues forming interactions represented by blue sticks, ligands represented by orange sticks. Interactions represented by straight lines and dotted lines (green-hydrogen bond, blue-hydrophobic, π-π stacking-orange. (A) PRMT5-docked with 3XV. (B) PRMT5-docked with TOP1. (C) PRMT5-docked with TOP2. (D) Three-dimensional stick representation of PRMT5 active site bound to 3XV. (E) Three-dimensional stick representation of PRMT5 active site bound to TOP1 (F) Three-dimensional stick representation of PRMT5 active site bound to TOP2.

Figure 4

RMSD plot of docked complexes generated through MDS at 200 ns. Gray—RMSD conformational dynamics analysis of APO. Green—RMSD conformational dynamics analysis of 3XV. Orange—RMSD conformational dynamics analysis of TOP1. Violet—RMSD conformational dynamics analysis of TOP2.

Figure 5

RMSF plot of docked complexes generated through MDS at 200 ns. Gray—RMSF conformational dynamics analysis of APO. Green—RMSF conformational dynamics analysis of 3XV. Orange—RMSF conformational dynamics analysis of TOP1. Violet—RMSF conformational dynamics analysis of TOP2.

Figure 6

Rg and SASA plots of docked complexes generated through MDS at 200 ns. Gray—Rg plot of PRMT5 in apo and complexed with APO. Green–Rg plot of PRMT5 in apo and complexed with 3XV. Orange—Rg plot of PRMT5 in apo and complexed with TOP1. Violet—Rg plot of PRMT5 in apo and complexed with TOP2.

Figure 7

H-bond analysis of docked complexes generated through MDS at 200 ns. Gray—Inter H-bond analysis of APO. Green—Inter H-bond analysis of 3XV. Orange—Inter H-bond analysis of TOP1. Violet—Inter H-bond analysis of TOP2.

Figure 8

PCA analysis of docked complexes generated through MDS at 200 ns. Gray—PCA analysis of APO. Green—PCA analysis of 3XV. Orange—PCA analysis of TOP1. Violet—PCA analysis of TOP2.

Figure 9

Three-dimensional stick representations of simulated docked complexes at different time intervals. (A) 3XV. (B) TOP1. (C) TOP2. Green line represents H-bond interaction. Red line represents hydrophobic interaction. Orange line represents π-π- stacking interaction. Yellow line represents cation-π stacking.