Structure-based virtual screening workflow to identify antivirals targeting HIV-1 capsid.

Area of Science:

• Virology
• Medicinal Chemistry
• Computational Chemistry

Background:

• The HIV-1 capsid protein is crucial for viral replication and serves as a key target for antiviral drug development.
• Existing capsid inhibitors offer a foundation, but novel compounds targeting new binding sites are needed to overcome resistance.

Purpose of the Study:

• To identify novel small molecules that inhibit HIV-1 capsid function by targeting the PF74 binding site.
• To explore a new sub-pocket at the capsid dimer interface for potential drug development.

Main Methods:

• A structure-based virtual screening workflow combining molecular docking and absolute binding free energy (ABFE) calculations was employed.
• 1.6 million compounds from the ZINC database were screened, followed by refinement using Binding Energy Distribution Analysis Method (BEDAM) and Double Decoupling methods.
• Thermal shift assays were used to experimentally validate the effect of identified compounds on HIV-1 capsid hexamer stability.

Main Results:

• The virtual screening workflow identified 24 potential HIV-1 capsid inhibitors with calculated binding free energies ranging from -6 to -12 kcal/mol.
• Two compounds, ZINC520357473 and ZINC4119064, significantly increased the melting point of the HIV-1 capsid hexamer by 14.8°C and 33°C, respectively.
• These validated hits suggest a novel binding mode at the capsid dimer interface, potentially occupying a previously unexploited sub-pocket.

Conclusions:

• ZINC520357473 and ZINC4119064 are promising primary hits for novel HIV-1 capsid inhibitors.
• The identified compounds and their binding mode offer new avenues for developing next-generation antiretroviral therapies.
• Further investigation into the binding interactions and optimization of these compounds is warranted.