Exploring the Therapeutic Axis of Antioxidant Alkaloids Against Sickle β-globin Mutation with Binding Site Engineering and Bioavailability

Background: Sickle cell anemia is a monogenic hemoglobinopathy caused by a mutation in the β-globin gene (hemoglobin subunit beta, HBB), leading to the production of hemoglobin S (HbS). Under deoxygenated conditions, HbS polymerizes abnormally, causing red blood cells to adopt a sickled shape. This results in vaso-occlusion, hemolysis, and chronic organ damage. Current treatment options remain limited, necessitating the identification of novel therapeutic agents that can target the molecular mechanisms underlying the disease. Objectives: This study aimed to investigate the therapeutic potential of 12 antioxidant alkaloids for targeting mutant HbS through a computational approach. The primary goal was to evaluate binding interactions, drug-likeness, and pharmacokinetic profiles to identify lead candidates for further development in sickle cell anemia therapy. Materials and Methods: Target validation of the HBB gene was performed using the STRING database to confirm its relevance in disease pathology. The three-dimensional structure of mutant HbS (Protein Data Bank ID: 2HBS) was retrieved and used to evaluate interactions with selected antioxidant alkaloids. Molecular interaction simulations were conducted to determine binding affinities, followed by drug-likeness screening based on Lipinski’s rule of five. Pharmacokinetic and bioavailability profiling was carried out using absorption, distribution, metabolism, excretion, and toxicity-based prediction tools. Results: The selected compounds exhibited binding affinities ranging from −5.5 to −10.7 kcal/mol, with rutaecarpine, harmine, and vindoline showing the strongest interactions with HbS. In total, 10 of the 12 compounds complied with druglikeness criteria. Pharmacokinetic modeling predicted favorable gastrointestinal absorption for most compounds, with no predicted blood–brain barrier penetration. Radar plot analysis revealed that vindoline, capsaicin, and harmine displayed optimal bioavailability profiles across key physicochemical parameters, indicating their suitability for oral administration. Conclusion: The study identified vindoline, harmine, and rutaecarpine as top candidate alkaloids with strong binding affinity, favorable pharmacokinetics, and bioavailability for therapeutic targeting of HbS. These findings support the continued exploration of natural antioxidant alkaloids as viable leads for developing novel interventions in sickle cell anemia, pending further in vitro and in vivo validation.