Quinoline-based Protein-protein Interaction Inhibitors of LEDGF/p75 and HIV Integrase: An In Silico Study

Area of Science:

• Drug Discovery and Development
• Structural Biology
• Computational Chemistry

Background:

• Integrase Strand Transfer Inhibitors (INSTIs) face resistance due to HIV integrase (IN) mutations.
• Allosteric integrase inhibitors (ALLINIs) offer a new therapeutic strategy by targeting IN-host cofactor interactions.
• Lens epithelium derived growth factor (LEDGF/p75) is a crucial host cofactor for IN, and inhibiting its interaction with IN is a promising approach.

Purpose of the Study:

• To correlate computational docking scores with in vitro biological activity for LEDGF/p75-IN interaction inhibitors (LEDGINs).
• To establish structure-activity relationships for quinoline-based LEDGINs.
• To guide the design of novel and potent anti-HIV agents targeting protein-protein interactions.

Main Methods:

• Hierarchical clustering was used to partition LEDGIN compounds into training and testing sets.
• Molecular docking simulations were performed to generate docking scores.
• The robustness of the predictive model was validated using q2 and r2 metrics.

Main Results:

• A correlation model was established between docking scores and in vitro biological data for quinoline-based LEDGINs.
• The model demonstrated robustness and predictive capability for compound activity.
• Virtual screening hits containing the quinoline scaffold were identified and their activities predicted.

Conclusions:

• The developed model effectively predicts the activity of LEDGINs based on docking scores.
• This approach facilitates the identification of potent anti-HIV agents by understanding structure-activity relationships.
• Targeting the LEDGF/p75-IN interaction interface with novel quinoline-based compounds shows therapeutic potential.