AncPhore: A versatile tool for anchor pharmacophore steered drug discovery with applications in discovery of new inhibitors targeting metallo
| Autor: | Qingqing, Dai, Yuhang, Yan, Xiangli, Ning, Gen, Li, Junlin, Yu, Ji, Deng, Lingling, Yang, Guo-Bo, Li |
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| Rok vydání: | 2020 |
| Předmět: |
ROC curve
receiver operating characteristic curve TNKS2 tankyrase 2 Metalloenzyme HA hydrogen-bond acceptor Tryptophan 2 3-dioxygenase RMSD root mean square deviation AUC area under the curve BRD4 bromodomain-containing protein 4 CatK cathepsin K GA genetic algorithm MB metal coordination HIV-P human immunodeficiency virus protease NDM new delhi MBL STK serine threonine kinase EX exclusion volume Metallo-β-lactamase IMP imipenemase MMP matrix metalloproteinase NE negatively charged center CA2 carbonic anhydrase 2 AR aromatic ring RT reverse transcriptase SSEL secondary structure element length IDO1 indoleamine 2 3-dioxygenase 1 Original Article RTK receptor tyrosine kinase HD hydrogen-bond donor Anchor pharmacophore CTS cathepsins CV covalent bonding NP without anchor pharmacophore features Virtual screening Indoleamine 2 3-dioxygenase MIC minimum inhibitory concentration EF enrichment factor TDO tryptophan 2 3-dioxygenase MAPK14 mitogen-activated protein kinase 14 MBL metallo-β-lactamase ROCK1 rho-associated protein kinase 1 VEGFR2 vascular endothelial growth factor receptor 2 VIM verona integron-encoded MBL AMPC asian mouse phenotyping consortium AP anchor pharmacophore SBL serine beta lactamase TDSS torsion-driving systematic search HIV1-P human immunodeficiency virus type 1 protease BACE1 beta-secretase 1 LE ligand efficiency CDK2 cyclin-dependent kinase 2 CA carbonic anhydrase MMP13 matrix metallopeptidase 13 PO positively charged center HY hydrophobic |
| Zdroj: | Acta Pharmaceutica Sinica. B |
| ISSN: | 2211-3835 |
| Popis: | We herein describe AncPhore, a versatile tool for drug discovery, which is characterized by pharmacophore feature analysis and anchor pharmacophore (i.e., most important pharmacophore features) steered molecular fitting and virtual screening. Comparative analyses of numerous protein–ligand complexes using AncPhore revealed that anchor pharmacophore features are biologically important, commonly associated with protein conservative characteristics, and have significant contributions to the binding affinity. Performance evaluation of AncPhore showed that it had substantially improved prediction ability on different types of target proteins including metalloenzymes by considering the specific contributions and diversity of anchor pharmacophore features. To demonstrate the practicability of AncPhore, we screened commercially available chemical compounds and discovered a set of structurally diverse inhibitors for clinically relevant metallo-β-lactamases (MBLs); of them, 4 and 6 manifested potent inhibitory activity to VIM-2, NDM-1 and IMP-1 MBLs. Crystallographic analyses of VIM-2:4 complex revealed the precise inhibition mode of 4 with VIM-2, highly consistent with the defined anchor pharmacophore features. Besides, we also identified new hit compounds by using AncPhore for indoleamine/tryptophan 2,3-dioxygenases (IDO/TDO), another class of clinically relevant metalloenzymes. This work reveals anchor pharmacophore as a valuable concept for target-centered drug discovery and illustrates the potential of AncPhore to efficiently identify new inhibitors for different types of protein targets. Graphical abstract A new versatile tool for pharmacophore-based drug discovery, termed AncPhore, is developed. The application of AncPhore led to identification of new structurally diverse inhibitors for clinically relevant metallo-β-lactamases and IDO1/TDO.Image 1 |
| Databáze: | OpenAIRE |
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