Effective screening strategy using ensembled pharmacophore models combined with cascade docking: application to p53-MDM2 interaction inhibitors.
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.
State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing, Jiangsu 210009, China.
Xin
X
Xue
Jin-Lian
JL
Wei
Li-Li
LL
Xu
Mei-Yang
MY
Xi
Xiao-Li
XL
Xu
Fang
F
Liu
Xiao-Ke
XK
Guo
Lei
L
Wang
Xiao-Jin
XJ
Zhang
Ming-Ye
MY
Zhang
Meng-Chen
MC
Lu
Hao-Peng
HP
Sun
Qi-Dong
QD
You
D001665:Binding Sites; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D014584:User-Computer Interface
D008024:Ligands; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2