Structural Basis of Antisickling Effects of Selected FDA Approved Drugs: A Drug Repurposing Study

• Published in: Current computer-aided drug design
• Main Authors: Olubiyi, Olujide O, Olagunju, Maryam O, Oni, James O, Olubiyi, Abidemi O
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01.01.2018
• Subjects: haemoglobin; drug repurposing; Sickle cell disease; molecular dynamics; effective energy
• ISSN: 1875-6697
• DOI: 10.2174/1573409914666180129163711

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. 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. 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.