Unveiling (−)‐Englerin A as a Modulator of L‐Type Calcium Channels

Abstract The voltage‐dependent L‐type Ca2+channel was identified as a macromolecular target for (−)‐englerin A. This finding was reached by using an unprecedented ligand‐based prediction platform and the natural product piperlongumine as a pharmacophore probe. (−)‐Englerin A features high substructure dissimilarity to known ligands for voltage‐dependent Ca2+ channels, selective binding affinity for the dihydropyridine site, and potent modulation of calcium signaling in muscle cells and vascular tissue. The observed activity was rationalized at the atomic level by molecular dynamics simulations. Experimental confirmation of this hitherto unknown macromolecular target expands the bioactivity space for this natural product and corroborates the effectiveness of chemocentric computational methods for prioritizing target‐based screens and identifying binding counterparts of complex natural products.

[1]  R. Fröhlich,et al.  Total synthesis and biological evaluation of (-)-englerin A and B: synthesis of analogues with improved activity profile. , 2011, Angewandte Chemie.

[2]  G. Schneider,et al.  Repurposing de novo designed entities reveals phosphodiesterase 3B and cathepsin L modulators. , 2015, Chemical communications.

[3]  Vladimir Poroikov,et al.  Multi-targeted natural products evaluation based on biological activity prediction with PASS. , 2010, Current pharmaceutical design.

[4]  A. Hopkins.  Network pharmacology: the next paradigm in drug discovery. , 2008, Nature chemical biology.

[5]  Michael J. Keiser,et al.  Relating protein pharmacology by ligand chemistry , 2007, Nature Biotechnology.

[6]  Boris S Zhorov,et al.  Structural Model for Dihydropyridine Binding to L-type Calcium Channels* , 2009, The Journal of Biological Chemistry.

[7]  Petra Schneider,et al.  Von komplexen Naturstoffen zu synthetisch leicht zugänglichen Mimetika mithilfe von computergestütztem De‐novo‐Design , 2016 .

[8]  William J. Chain,et al.  A brief synthesis of (-)-englerin A. , 2011, Journal of the American Chemical Society.

[9]  G. Schneider,et al.  Revealing the Macromolecular Targets of Fragment-Like Natural Products. , 2015, Angewandte Chemie.

[10]  Petra Schneider,et al.  Identifying the macromolecular targets of de novo-designed chemical entities through self-organizing map consensus , 2014, Proceedings of the National Academy of Sciences.

[11]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[12]  Herbert Waldmann,et al.  (-)-Englerin A is a potent and selective activator of TRPC4 and TRPC5 calcium channels. , 2015, Angewandte Chemie.

[13]  宁北芳,et al.  疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A , 2005 .

[14]  Mathias Dunkel,et al.  SuperPred: update on drug classification and target prediction , 2014, Nucleic Acids Res..

[15]  K. Gustafson,et al.  Englerin A, a selective inhibitor of renal cancer cell growth, from Phyllanthus engleri. , 2009, Organic letters.

[16]  A. Harvey,et al.  The re-emergence of natural products for drug discovery in the genomics era , 2015, Nature Reviews Drug Discovery.

[17]  Petra Schneider,et al.  From Complex Natural Products to Simple Synthetic Mimetics by Computational De Novo Design. , 2016, Angewandte Chemie.

[18]  T. Golub,et al.  Selective killing of cancer cells with a small molecule targeting stress response to ROS , 2011, Nature.

[19]  John P. Overington,et al.  The promise and peril of chemical probes. , 2015, Nature chemical biology.

[20]  J. E. Glynn,et al.  Numerical Recipes: The Art of Scientific Computing , 1989 .

[21]  Herbert Waldmann,et al.  Biology-oriented synthesis: harnessing the power of evolution. , 2014, Journal of the American Chemical Society.

[22]  J. Aubé,et al.  Probing Chemical Space with Alkaloid-Inspired Libraries , 2014, Nature chemistry.

[23]  Petra Schneider,et al.  Counting on natural products for drug design. , 2016, Nature chemistry.

[24]  S. Fulle,et al.  Effect of milrinone analogues on intracellular calcium increase in single living H9C2 cardiac cells. , 2010, European journal of medicinal chemistry.

[25]  Petra Schneider,et al.  Revealing the macromolecular targets of complex natural products. , 2014, Nature chemistry.

[26]  Petra Schneider,et al.  Chemically Advanced Template Search (CATS) for Scaffold-Hopping and Prospective Target Prediction for ‘Orphan’ Molecules , 2013, Molecular informatics.

[27]  Stefan Wetzel,et al.  Bioactivity-guided mapping and navigation of chemical space. , 2009, Nature chemical biology.