Drug Design, Molecular Docking and Dynamics Studies on the Interaction of Voxelotor, L- Glutamine and Hydroxy Urea with Human Carbonmonoxy Hemoglobin S

Abstract

Abstract Sickel cell disease (SCD) is a defect in hemoglobin structure that leads to deficiency in oxygen transfer in the body. Voxelotor, L- Glutamine and Hydroxyurea are three out of the four drugs approved by the FDA to treat SCD, yet the disease is incurable. The medical community are searching for new drug and new drug target that can cure or inhibit the product of this disease. In this research, we used molecular docking, molecular dynamics (MD) simulation and ADMET studies to analyze the interactions of these drugs. MD potential of the three drugs into the active site of hemoglobin S was investigated. Voxelotor has the highest score, with a binding energy of -21.66 kcalmol-1. Out of the Eight new drug designed based on the backbone of Voxelotor, it was found out that Vox8 has the best binding energy of -24.73 kcalmol-1, followed by Vox7 with binding energy of -22.30 kcalmol-1 and Vox4 with -21.81 kcalmol-1 respectively. The docking results were validated with the aid of MD simulations, the results revealed that the complex of the ligand and the receptor protein is stable at 300K. For the prediction of blood-brain barrier penetration, the SwissADMET web based service was able to predict the BBB profile for the designed drugs, Lipinski’s rule was obeyed, bioavailability Score were good which led to the understanding of the biological activities of the compounds.