期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 53, 期 10, 页码 2715-2729出版社
AMER CHEMICAL SOC
DOI: 10.1021/ci400348f
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资金
- National Natural Science Foundation of China [81230078, 81202463, 91129732]
- Program of State Key Laboratory of Natural Medicines
- China Pharmaceutical University [JKGQ201103]
- 863 program [2012AA020301]
- National Major Science and Technology Project of China (Innovation and Development of New Drugs) [2013ZX09402-102-001-005, 2010ZX09401-401]
Protein-protein interactions (PPIs) play a crucial role in cellular function and form the backbone of almost all biochemical processes. In recent years, protein-protein interaction inhibitors (PPIIs) have represented a treasure trove of potential new drug targets. Unfortunately, there are few successful drugs of PPIIs on the market. Structure-based pharmacophore (SBP) combined with docking has been demonstrated as a useful Virtual Screening (VS) strategy in drug development projects. However, the combination of target complexity and poor binding affinity prediction has thwarted the application of this strategy in the discovery of PPIIs. Here we report an effective VS strategy on p53-MDM2 PPI. First, we built a SBP model based on p53-MDM2 complex cocrystal structures. The model was then simplified by using a Receptor-Ligand complex-based pharmacophore model considering the critical binding features between MDM2 and its small molecular inhibitors. Cascade docking was subsequently applied to improve the hit rate. Based on this strategy, we performed VS on NCI and SPECS databases and successfully discovered 6 novel compounds from 15 hits with the best, compound 1 (NSC 5359), K-i = 180 +/- 50 nM. These compounds can serve as lead compounds for further optimization.
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