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

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• 作者：Dr. Tiago Rodrigues ; Dr. Florian Sieglitz ; Dr. Ví ; ctor J. Somovilla ; Dr. Pedro M. S. D. Cal ; Prof. Dr. Antony Galione ; Dr. Francisco Corzana and Dr. Gon&#231 ; alo J. L. Bernardes
• 刊名：Angewandte Chemie International Edition
• 出版年：2016
• 出版时间：September 5, 2016
• 年：2016
• 卷：55
• 期：37
• 页码：11077-11081
• 全文大小：2431K
• ISSN：1521-3773

文摘

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.