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Molecules. 2024 Jun 4;29(11):2662. doi: 10.3390/molecules29112662.
The Discovery of Selective Protein Arginine
Methyltransferase 5 Inhibitors in the Management of
β-Thalassemia through Computational Methods
Bishant Pokharel 1 , Yuvaraj Ravikumar 1 , Lavanyasri Rathinavel 2 , Teera Chewonarin 1 ,
Monsicha Pongpom 3 , Wachiraporn Tipsuwan 4 , Pimpisid Koonyosying 1 ,
Somdet Srichairatanakool 1
Affiliations
PMID: 38893537 PMCID: PMC11173459 DOI: 10.3390/molecules29112662
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 βthalassemia.
Keywords: PRMT5 inhibitors; dynamics; fetal hemoglobin; molecular docking; simulations; βthalassemia.
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Figure 3 Illustration of
Figure 1 ( A )
Figure 2 ( A ) Cartoon
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PRMT5-docked with
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Figure 4 RMSD plot of
Figure 5 RMSF plot of
Figure 6 Rg and SASA
Suppression of…
docked complexes…
docked complexes…
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