In Silico Discovery of Potential Inhibitors Targeting the RNA Binding Loop of ADAR2 and 5-HT2CR from Traditional Chinese Natural Compounds
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Date
2023
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Int. J. Mol. Sci.
Abstract
Adenosine deaminase acting on RNA 2 (ADAR2) is an important enzyme involved in
RNA editing processes, particularly in the conversion of adenosine to inosine in RNA molecules.
Dysregulation of ADAR2 activity has been implicated in various diseases, including neurological
disorders (including schizophrenia), inflammatory disorders, viral infections, and cancers. Therefore,
targeting ADAR2 with small molecules presents a promising therapeutic strategy for modulating
RNA editing and potentially treating associated pathologies. However, there are limited compounds
that effectively inhibit ADAR2 reactions. This study therefore employed computational approaches
to virtually screen natural compounds from the traditional Chinese medicine (TCM) library. The
shortlisted compounds demonstrated a stronger binding affinity to the ADAR2 (<−9.5 kcal/mol)
than the known inhibitor, 8-azanebularine (−6.8 kcal/mol). The topmost compounds were also
observed to possess high binding affinity towards 5-HT2CR with binding energies ranging from
−7.8 to −12.9 kcal/mol. Further subjecting the top ADAR2–ligand complexes to molecular dynamics
simulations and molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations
revealed that five potential hit compounds comprising ZINC000014637370, ZINC000085593577,
ZINC000042890265, ZINC000039183320, and ZINC000101100339 had favorable binding free energies
of −174.911, −137.369, −117.236, −67.023, and −64.913 kJ/mol, respectively, with the human ADAR2
protein. Residues Lys350, Cys377, Glu396, Cys451, Arg455, Ser486, Gln488, and Arg510 were also
predicted to be crucial in ligand recognition and binding. This finding will provide valuable insights
into the molecular interactions between ADAR2 and small molecules, aiding in the design of future
ADAR2 inhibitors with potential therapeutic applications. The potential lead compounds were also
profiled to have insignificant toxicities. A structural similarity search via DrugBank revealed that
ZINC000039183320 and ZINC000014637370 were similar to naringin and naringenin, which are
known adenosine deaminase (ADA) inhibitors. These potential novel ADAR2 inhibitors identified
herein may be beneficial in treating several neurological disorders, cancers, viral infections, and
inflammatory disorders caused by ADAR2 after experimental validation
Description
Research Article
Keywords
adenosine deaminases acting on RNA (ADAR), anti-ADAR2, natural products, depression