Direct interaction between ABCA1 and HIV-1 Nef: Molecular modeling and virtual screening for inhibitors
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Updated: Oct 18, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Alexei A Adzhubei1, Amol Kulkarni2, Anna P Tolstova1
1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
Insights
HIV-1 infection disrupts cholesterol transport by affecting the ABCA1 protein. This study models the interaction between HIV-1 Nef and ABCA1, identifying potential inhibitors for related co-morbidities.
Area of Science:
- Molecular Biology
- Virology
- Biochemistry
Background:
- HIV-1 infection impairs cellular cholesterol efflux via downmodulation of the ABCA1 transporter.
- This impairment contributes to metabolic co-morbidities, particularly cardiovascular disease.
- The HIV-1 protein Nef is implicated in ABCA1 downmodulation, primarily through disrupting its interaction with calnexin, leading to ABCA1 degradation.
Purpose of the Study:
- To develop an optimized model of the Nef:ABCA1 interaction.
- To identify specific interaction sites between Nef and ABCA1.
- To enable virtual screening for potential inhibitors of this interaction.
Main Methods:
- Development of an optimized computational model for Nef:ABCA1 interaction.
- Identification of interaction sites on both Nef and ABCA1.
- Virtual screening using docking simulations to identify potential inhibitory compounds.
Main Results:
- The study successfully modeled the Nef:ABCA1 interaction, pinpointing key interaction sites.
- Predicted Nef interaction sites for ABCA1 overlap with those involved in Nef:calnexin interaction.
- Compounds previously shown to inhibit Nef:calnexin interaction ranked highly in docking simulations against Nef's ABCA1-interacting sites.
Conclusions:
- The findings suggest that the same chemical compounds may inhibit both Nef:ABCA1 and Nef:calnexin interactions.
- This study identifies a series of compounds with potential for development as inhibitors of Nef-mediated co-morbidities in HIV infection.
- Targeting the Nef:ABCA1 interaction offers a novel therapeutic strategy for managing HIV-associated metabolic complications.
Abstract:
HIV-1 infection impairs cellular cholesterol efflux by downmodulating the cholesterol transporter ABCA1, leading to metabolic co-morbidities like cardio-vascular disease. The main mechanism of this effect is impairment by the HIV-1 protein Nef of the ABCA1 interaction with the endoplasmic reticulum chaperone calnexin, which leads to a block in ABCA1 maturation followed by its degradation. However, ABCA1 is also downmodulated by Nef delivered with the extracellular vesicles, suggesting involvement of a direct Nef:ABCA1 interaction at the plasma membrane. Here, we present an optimized model of the Nef:ABCA1 interaction, which identifies interaction sites and provides an opportunity to perform a virtual screening for potential inhibitors. Interestingly, the predicted sites on Nef involved in the ABCA1 interaction overlap with those involved in the interaction with calnexin. The compounds previously shown to block Nef:calnexin interaction were among the top ranking ligands in docking simulations with ABCA1-interacting sites on Nef, suggesting the possibility that both interactions can be inhibited by the same chemical compounds. This study identifies a series of compounds for potential development as inhibitors of Nef-mediated co-morbidities of HIV infection.
