Computational Studies of 5-methoxypsolaren as Potential Deoxyhemoglobin S Polymerization Inhibitor
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Abstract
Ficus thonningii is a native Southeast Nigerian tree. The leaves are medicinal, and it is reportedly used in sickle cell disease (SCD) management by ethnic people of Ebonyi State, Southeast, Nigeria. Previously we characterized the in vitro antisickling activity of its crude leaf methanol extract and observed that it functioned via the sickle polymerization inhibition pathway and 5-methoxypsolaren (5-MPS) labelled FTH1 was isolated as one of its constituents. Therefore, this research aim and objectives are to comprehend in silico the mechanism of the observed in vitro sickle deoxyhemoglobin (DeOxyHbS) polymerization inhibitory activity of 5-MPS. The structure of the target protein (2HBS) was chosen based on advanced BLAST analysis. Molecular docking and molecular dynamics simulation studies were carried out using blind docking and distant-dependent dielectric assays, respectively whereas ADMET was performed using SwissADME and protox-II webserver. The ability of 5-MPS to interfere with the processes that leads to DeOxyHbs polymerization was evident in the binding affinity of -6.4 Kcal/mol. The MD simulation analysis of the binding site amino acid residue confirmed its antisickling potentials due to observed variation in perturbation between the bound (DeOxyHbS-5-MPS) and unbound (DeOxyHbS) simulation studies whereas the ADMET showed that 5-MPS is a potential CYP1A2 and CYP2D6 inhibitor. The results suggest that 5-MPS is a potential antisickling drug candidate.
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