[KSCI] Korea Science Citation Index Service

http://dx.doi.org/10.5012/bkcs.2014.35.7.2097

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)

Bao, Guang-Kai (College of Chemical Engineering, Sichuan University)
Zhou, Lu (College of Chemical Engineering, Sichuan University)
Wang, Tai-Jin (College of Chemical Engineering, Sichuan University)
He, Lu-Fen (College of Chemical Engineering, Sichuan University)
Liu, Tao (College of Chemical Engineering, Sichuan University)

Publication Information

Bulletin of the Korean Chemical Society / v.35, no.7, 2014 , pp. 2097-2108 More about this Journal

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.

Keywords

Mcl-1 inhibitors; Pharmacophore model; Molecular docking; Molecular dynamics simulation;

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