Construction and application of 3D-pharmacophore model of glucokinase agonists

TANG Chunlei; HUANG Wenlong; QIAN Hai

doi:10.11665/j.issn.1000-5048.20150208

Journal of China Pharmaceutical University > 2015 > 46(2): 181-187. > DOI: 10.11665/j.issn.1000-5048.20150208

TANG Chunlei, HUANG Wenlong, QIAN Hai. Construction and application of 3D-pharmacophore model of glucokinase agonists[J]. Journal of China Pharmaceutical University, 2015, 46(2): 181-187. DOI: 10.11665/j.issn.1000-5048.20150208

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Construction and application of 3D-pharmacophore model of glucokinase agonists

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Abstract

Glucokinase(GK), which plays a pivotal role in maintaining glucose equilibrium in the human body, emerged as one of the most promising targets for the treatment of diabetes mellitus type 2. Pharmacophore models of glucokinase agonist inhibitors have been generated with a training set of 25 glucokinase agonists(EC₅₀ values from 2 to 78 000 nmol/L)using Discovery studio 2. 5. The best hypothesis contained three hydrogen bond acceptors, one hydrophobic center, and three excluded volumes with a correlation coefficient of 0. 955, cost difference of 60. 5, RMSD of 0. 714. This model was validated by test set, Fischer randomization test and decoy set methods. Pharmacophore model was also utilized as a three dimentional query to screen in-house andrographolide derivative database. New potential GK agonist was obtained therewith, and the hit compound is capable for further screening assay studies. Preliminary biological evaluation suggests that this new pharmacophore model fuctions superiorly in virtual screening.
- glucokinase,
- pharmacophore model,
- andrographolide derivatives,
- virtual screening

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