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


Download PDF Flyer




Combinatorial Chemistry & High Throughput Screening

Aims & ScopeAbstracted/Indexed in

Ranking and Category:
  • 23rd of 71 in Chemistry, Applied

Submit Abstracts Online Submit Manuscripts Online

Editor-in-Chief:
Rathnam Chaguturu
iDDPartners, 3 Edith Court
Princeton Junction
NJ 08550
USA


View Full Editorial Board

Subscribe Purchase Articles Order Reprints

Current: 1.925
5 - Year: 1.782

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, Kancheepuram District, Chennai, 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 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, rheumatoid arthritis.

Purchase Online Rights and Permissions

  
  



Article Details

Volume: 17
Issue Number: 8
First Page: 663
Last Page: 673
Page Count: 11
DOI: 10.2174/1386207317666140321115128
Advertisement

Related Journals




Webmaster Contact: urooj@benthamscience.org Copyright © 2014 Bentham Science