E-Pharmacophore and Molecular Dynamics Study of Flavonols and Dihydroflavonols as Inhibitors against DiHydroOrotate DeHydrogenase

ISSN: 1875-5402 (Online)
ISSN: 1386-2073 (Print)


Volume 17, 10 Issues, 2014


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Combinatorial Chemistry & High Throughput Screening

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E-Pharmacophore and Molecular Dynamics Study of Flavonols and Dihydroflavonols as Inhibitors against DiHydroOrotate DeHydrogenase

Author(s): Priya Swaminathan, Sukesh Kalva and Lilly M Saleena

Affiliation: Department of Bioinformatics, SRM University, Kattankulathur, Tamilnadu- 603203, India

Abstract

DiHydroOrotate DeHydrogenase [huDHODH] is a therapeutic target for Rheumatoid arthritis [RA]. Leflunomide [A771726] is a widely used synthetic inhibitor against huDHODH. We suggest a method where scaffold of Leflunomide is searched against a photochemical database 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 molecules of huDHODH by assigning higher fitness score. A reverse validation was also performed where random 4 featured Pharmacophore were built and its efficiency in identifying actives was compared with our E-Pharmacophore. Our E-pharmacophore was very efficient, since it passed both validations by picking the known active molecules with high fitness scores. This validated E- pharmacophore is searched against the KEGG phytochemicals subset. The 18 similar molecules were subjected to docking with huDHODH. The molecules with docking score greater than 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, 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


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Article Details

Volume: 17
First Page: 1
Page Count: 1
DOI: 10.2174/1386207317666140321115128
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