Identification of ligands for RNA targets via structure-based virtual screening: HIV-1 TAR

Area of Science:

• Computational chemistry
• Molecular biology
• Drug discovery

Background:

• The Tat protein binding to TAR RNA is essential for HIV-1 replication.
• Identifying small molecules that disrupt this interaction is a key strategy for developing antiviral therapies.

Purpose of the Study:

• To develop and validate a computational screening procedure for identifying ligands that bind to the HIV-1 TAR RNA structure.
• To discover novel inhibitors of the Tat-TAR interaction.

Main Methods:

• A four-step molecular docking procedure (rigid and flexible) was employed to screen the Available Chemicals Directory (ACD).
• An empirical binding free energy function, incorporating solvation and entropic effects, was developed and validated.
• Virtual screening of the ACD for TAR RNA ligands was performed, followed by experimental validation of top-ranked compounds.

Main Results:

• The computational procedure successfully docked known ligands for five RNA complexes, validating its efficacy.
• The binding free energy function demonstrated high accuracy, ranking the native ligand 17th out of ~153,000 compounds for an RNA aptamer.
• Screening identified known TAR ligands and suggested novel potential ligands, with two exhibiting significant inhibition (IC50 ~1 microM) of the Tat-TAR interaction.

Conclusions:

• The developed computational docking and free energy calculation method is effective for identifying RNA-binding ligands.
• This approach can significantly reduce the search space for potential antiviral drug candidates targeting HIV-1.
• Two novel compounds show promise as inhibitors of the critical Tat-TAR interaction in HIV-1.