E-Pharmacophore and Molecular Dynamics Study of Flavonols and Dihydroflavonols as Inhibitors Against DiHydroOrotate DeHydrogenase
Lilly M. Saleena.
DiHydroOrotate DeHydrogenase [huDHODH] is a therapeutic target for Rheumatoid arthritis [RA].
Leflunomide [A771726] is a widely used synthetic inhibitor against huDHODH. We to find more efficient lead like
compounds. A four featured E-Pharmacophore A1D4H6R7 was built based on the inhibitor A771726. This
pharmacophore was validated by checking its ability to identify known highly active inhibitors of huDHODH and
assigning higher fitness scores to them. A reverse validation was also performed where random 4 featured
pharmacophores were built and its efficiency in identifying actives was compared with our E-Pharmacophore. Our Epharmacophore
was very efficient, since it passed both validations by picking the known active molecules with high
fitness scores. This validated E- pharmacophore was searched against the KEGG phytochemicals subset database. This
search resulted in 18 molecules which were subjected to docking with huDHODH. The molecules with docking score
greater than that of A771726 were selected. The docking results were further validated using MM/GBSA which gave
similar ranking with high binding free energy values. The four molecules 6-Methoxytaxifolin, Rhamnetin, Rhamnazin and
Pinoquercetin were taken for explicit 3ns simulation and it was observed that all four molecules had acceptable RMSD
values and stable interactions. Thus our study, suggests four phytomolecules that might inhibit huDHODH more
efficiently than A771726. Interestingly, some of the obtained hits have already been proven in vitro anti-inflammatory
activity which confirms that, the developed E-pharmacophore can be used to identify novel small molecules against
inflammatory target, huDHODH.
Keywords: A771726, DiHydroOrotate DeHydrogenase, E-pharmacophore validation, MM/GBSA, molecular dynamics,
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