Natural Product-Derived Disruption of the HIV-1 Integrase–LEDGF/p75 Complex: Molecular Insights into the Inhibitory Potential of Guanipiperazine B

HIV integrase is an essential enzyme responsible for incorporating viral DNA into the host’s genome, a vital phase in the HIV replication process. The host protein, Lens Epithelium-Derived Growth Factor p75 (LEDGF/p75), connects with the HIV Integrase (IN) Catalytic Core Domain (CCD) via its Integrase Binding Domain (IBD) and anchors the pre-integration complex, aiding in the integration of HIV into regions of chromatin that are transcriptionally active. This interaction underscores the importance of the integrase-LEDGF/p75 complex as a target for therapeutic intervention. Interrupting this interaction with allosteric inhibitors of the LEDGF/p75-IN interaction, known as LEDGINs, has become a promising method to curb HIV replication. Although LEDGINs are still being studied for clinical application, they may be too costly for developing countries if approved, emphasizing the necessity for ongoing research into alternative methods. Natural substances like terpenes and flavonoids show antiviral properties. Consequently, utilizing natural compound libraries to target the HIV integrase-LEDGF/p75 interaction offers a new strategy for creating effective antiviral medications. This research assessed a collection of compounds derived from natural sources. To refine a library of over 76,000 compounds, Lipinski’s rule of five was applied. Molecular docking and 300 ns Molecular Dynamics (MD) simulations were conducted to pinpoint compounds with strong binding affinity and stability to the CCD-IBD interface, using LEDGIN6 as a benchmark inhibitor. Through molecular docking studies, Guanipiperazine B, CHEBI:211233 and Okaramine T were identified as promising inhibitors of the HIV-1 integrase-LEDGF/p75 complex, showing stronger binding affinities compared to the reference drug LEDGIN6. Among these, Guanipiperazine B exhibited the most stable binding, as evidenced by the lowest Root Mean Square Deviation (RMSD) and RMSF values in MD simulations, indicating robust and stable interactions. The binding free energy of Guanipiperazine B was the most favorable at −33.2 kcal/mol, as confirmed by thermodynamic analysis using the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) method, with van der Waals and electrostatic interactions contributing to this result. In contrast, LEDGIN6 and 15-Deoxyoxalicine A displayed weaker binding affinities, suggesting less effective interactions, although other compounds like CHEBI:211233 and Okaramine T also demonstrated positive binding characteristics and interactions. In summary, Guanipiperazine B emerged as the compound with the most favorable binding free energy and the least structural instability, marking it as a prime candidate for further therapeutic investigation and development. Although LEDGIN6 exhibited less favorable interactions, the results offer valuable insights for structural modifications to enhance efficacy. The integrase-LEDGF/p75 complex inhibitors introduced in this study hold the potential to disrupt the protein-protein interaction between HIV integrase and the LEDGF/p75 protein in vivo. To further validate these findings, future research should prioritize experimental studies to assess their therapeutic potential against HIV and their viability for clinical application.