期刊
FUTURE MEDICINAL CHEMISTRY
卷 9, 期 11, 页码 1141-1159出版社
FUTURE SCI LTD
DOI: 10.4155/fmc-2017-0061
关键词
acetycholineesterase; enzyme bioassay; ligand-receptor contact analysis; pharmacophore; PKC-theta; simulated annealing molecular dynamics
资金
- University of Jordan, King Abdullah II Fund for Development (KAFD)
- IMAN1 Center - Jordan's National Supercomputing Center
Aim: Ligand-based pharmacophore modeling requires long list of inhibitors, while pharmacophores based on single ligand-receptor crystallographic structure can be too restricted or promiscuous. Methodology: This prompted us to combine simulated annealing molecular dynamics (SAMD) with ligand-receptor contacts analysis as means to construct pharmacophore model(s) from single ligand-receptor complex. Lingand-receptor contacts that survive numerous heating-cooling SAMD cycles are considered critical and are used to guide pharmacophore development. Results: This methodology was implemented to develop pharmacophores for acetylcholinesterase and protein kinase C-theta. The resulting models were validated by receiver-operating characteristic analysis and in vitro bioassay. Assay identified four new protein kinase C-theta inhibitors among captured hits, two of which exhibited nanomolar potencies. Conclusion: The results illustrate the ability of the new method to extract valid pharmacophores from single ligand-protein complex.
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