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Bulletin of the Korean Chemical Society (BKCS)

ISSN 0253-2964(Print)
ISSN 1229-5949(Online)
Volume 35, Number 7
BKCSDE 35(7)
July 20, 2014 

 
Title
A Combined Pharmacophore-Based Virtual Screening, Docking Study and Molecular Dynamics (MD) Simulation Approach to Identify Inhibitors with Novel Scaffolds for Myeloid cell leukemia (Mcl-1)
Author
Guang-kai Bao, Lu Zhou*, Tai-jin Wang, Lu-fen He, Tao Liu
Keywords
Mcl-1 inhibitors, Pharmacophore model, Molecular docking, Molecular dynamics simulation
Abstract
Chemical feature based quantitative pharmacophore models were generated using the HypoGen module implemented in DS2.5. The best hypothesis, Hypo1, which was characterized by the highest correlation coefficient (0.96), the highest cost difference (61.60) and the lowest RMSD (0.74), consisted of one hydrogen bond acceptor, one hydrogen bond donor, one hydrophobic and one ring aromatic. The reliability of Hypo1 was validated on the basis of cost analysis, test set, Fischer’s randomization method and GH test method. The validated Hypo1 was used as a 3D search query to identify novel inhibitors. The screened molecules were further refined by employing ADMET, docking studies and visual inspection. Three compounds with novel scaffolds were selected as the most promising candidates for the designing of Mcl-1 antagonists. Finally, a 10 ns molecular dynamics simulation was carried out on the complex of receptor and the retrieved ligand to demonstrate that the binding mode was stable during the MD simulation.
Page
2097 - 2108
Full Text
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