Computational Evaluation of ADMET Properties and Molecular Docking Studies on Cryptolepine Analogs as Inhibitors of HIV Integrase

Background: HIV/AIDS remains a global health challenge, demanding innovative antiretroviral strategies. HIV integrase inhibition, a promising therapeutic target, warrants exploration. This study investigates the potential of Cryptolepine and analogues as integrase inhibitors through in-silico docking and ADMET profiles. Docking simulations reveal binding affinities, guiding rational drug design. ADMET predictions assess the pharmacokinetics, ensuring clinical viability. Cryptolepine and analogues show promise, offering a pathway for therapeutic development against HIV/AIDS. Further, insights contribute to ongoing efforts in combating the pandemic with effective antiretroviral strategies. Methods: Molecular docking investigations utilized Molegro Virtual Docker [MVD] 6.0, with the target protein [PDB ID: 1QS4] obtained from the Protein Data Bank. Ligands, particularly Cryptolepine- based, were selected from PubChem with adherence to Lipinski's Rule of Five for druglike properties. Computational tools, including pkCSM, aided ADMET profiling. This study, conducted on an AMD Ryzen 3 3200U computer with Windows 10 home, enhances understanding and potential therapeutic strategies against HIV/AIDS. Results: From a virtual screening of the PubChem database, the top ten candidates were selected based on their MolDock scores against the target 1QS4. All compounds had MolDock scores greater than -70.00 kcal, with [01] RPA 1 exhibiting the highest MolDock Score [-83.85 kcal] and Rerank Score [-39.59 kcal]. These compounds possessed the essential pharmacophore for HIV integrase inhibition against 1QS4. However, three compounds, including [01] RPA 1, [00] RPA 1_6, and [04] RPA 1_1, showed no hydrogen bonding interactions with Val 79 and Val 150 amino acid residues. This highlights the importance of structural analysis in understanding ligand-receptor interactions for rational drug design against HIV integrase. Conclusion: This study investigates how Cryptolepine analogues inhibit HIV integrase via docking and ADMET analysis. All analogues exhibit strong binding, especially those within the 400- 500 Da range. Specific amino acids and hydrogen bonds influence interactions. Compound [01] RPA 1_3 shows high intestinal absorption and promising properties, making it a potential HIV integrase inhibitor. The study highlights the importance of a comprehensive ADMET profile in drug development and suggests further exploration of [01] RPA 1_3 for HIV/AIDS therapy.