Introduction: In sickle cell anemia, deoxygenated HbS molecules polymerize into long fibers in the deep tissues during hypoxia. This leads to sickling of erythrocytes and clogging of capillaries and vessels. We are searching for new ligands like gbt440 that inhibit the HBS polymerization.
Methods and material: We obtain the molecular model of hemoglobin [PDB ID: 1NEJ] from the Protein Data Bank. We obtain the molecular model of GBT440 and curcumin from the PubChem database. The physicochemical properties are investigated using SwissADME software, then the docking for the protein-ligand binding sites and their affinity is performed. Finally, the molecular dynamics simulation is performed to determine the stability of the protein-ligand complex in the alpha-cleft of the hemoglobin tetramer model [Pdb ID: 1NEJ].
Results and Discussion: The docking results show that curcumin can bind with higher affinity than GBT440 to the near binding site of gbt440 in the alpha-cleft of the hemoglobin model. The hydrogen bonding and electrostatic interactions of the 1NEJ-GBT440 complex are different from the hydrogen and electrostatic interactions between the 1NEJ-curcumin complex. The result of the molecular dynamics simulation shows no clear difference in the flexibility of hemoglobin between the different complexes of ligands and hemoglobin.
Conclusion: the binding of curcumin to hemoglobin in the alpha cleft may inhibit the transition of hemoglobin to tense state and stabilize the hemoglobin tetramer model [PDB ID: 1NEJ] in the R2 state, but this issue should be investigated in the laboratory.