Molecular docking studies of Entada abyssinia phytochemicals as trypanosoma transferrin receptor inhibitors in Trypanosoma brucei

Abstract

Background: Human African trypanosomiasis (HAT), caused by Trypanosoma brucei subspecies (T. b. gambiense and T. b. rhodesiense), is a major health challenge in sub-Saharan Africa, particularly in Uganda. Current treatments, such as melarsoprol and suramin, are hindered by toxicity, drug resistance, and complex administration. The trypanosomal transferrin receptor (TfR), essential for parasite iron uptake, is a promising therapeutic target due to its structural divergence from human TfR, offering potential for selective inhibition. Main objective: To evaluate the binding affinity of 25 Entada abyssinica phytochemicals to the T. brucei TfR and assess their pharmacokinetic and electronic properties for potential anti-trypanosomal drug development. Methods: Molecular docking was performed using AutoDock Vina to assess the binding of 25 Entada abyssinica phytochemicals to the T. brucei TfR (PDB ID: 6SOY), with deferoxamine and the co-crystallized ligand as controls. Pharmacokinetic properties were evaluated using SwissADME. Density functional theory (DFT) analysis, conducted with Gaussian 09 at the B3LYP/6-31G (d,p) level, determined quantum chemical descriptors, including HOMO-LUMO gap, electronegativity, electrophilicity, hardness, and softness. Results: Quercetin-3-O-β-D-glucosyl (1→4)-α-1-rhamnoside and quercetin 3'-methylether exhibited superior binding energies (-8.9 and -8.5 kcal/mol, respectively) compared to deferoxamine (-6.1 kcal/mol) and the co-crystallized ligand (-7.2 kcal/mol), with favorable hydrogen bonding and hydrophobic interactions. Most compounds complied with Lipinski’s and Veber’s Rules, indicating good oral bioavailability, except deferoxamine and quercetin-3-O-α-1-rhamnoside. Quercetin 3'-methylether and quercetin-3-O-β-D-glucosyl (1→4)-α-1-rhamnoside showed high gastrointestinal absorption but inhibited CYP1A2/CYP2D6, suggesting potential drug-drug interactions. DFT analysis revealed quercetin 3'-methylether with the smallest HOMO-LUMO gap (3.682 eV), highest electrophilicity (3.691 eV), highest softness (0.555 eV⁻¹), and lowest hardness (1.801 eV), indicating high reactivity. Conversely, the co-crystallized ligand and quercetin-3-O-α-1-rhamnoside had larger gaps (6.003 eV), suggesting greater stability. Conclusion: These phytochemicals show promise as TfR inhibitors, warranting further invitro and invivo validation for anti-trypanosomal drug development