Abstract
Introduction: Sickle cell disease is characterized by a point mutation involving substitution of glutamic acid at position 6 to valine. Encoded in this hydrophobic mutation is both an intrinsic capacity for the beta globin molecules to assemble into thermodynamically favoured polymeric states as well as a rational way of interrupting the aggregation.
Methods: In this work, starting with a theoretical model that employs occlusive binding onto the beta globin aggregation surface and using a range of computational methods and an effective energy for screening, a number of FDA approved drugs with computed aggregation inhibitory activities were identified.
Results and Conclusion: The validity of the model was confirmed using sickling tests, after which pharmacophore models as well the structural basis for the observed antisickling effects were identified.
Keywords: Sickle cell, mutation, beta globin, pharmacophore models, antisickling, glutamic acid.
Graphical Abstract
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