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.

Machine intelligence decrypts β-lapachone as an allosteric 5-lipoxygenase inhibitor

“…The approach had been validated with NPs, to which new biology was inferred. 5 , 7 , 13 , 14 In contrast to other tools using structural fingerprints, 15 , 16 several targets were confidently predicted for 1 with SPiDER 12 ( cf. ESI † ).…”

“…As part of our NP target identification program, we set out to investigate the pharmacology of 1 . We employed a machine learning method (SPiDER) 12 , 13 that uses a consensus of self-organizing maps built from physicochemical and pharmacophore features. Tessellation of the chemical feature space provides an intuitive means for data visualization and prediction of potential drug target counterparts.…”

Na+ entry through heteromeric TRPC4/C1 channels mediates (−)Englerin A-induced cytotoxicity in synovial sarcoma cells

“…EA is a sesquiterpene extracted from Phyllanthus engleri . Although EA is a potent inhibitor of renal cancer cell growth, there are wide discussions regarding the mechanism involved 2 – 7 , 26 – 28 . In this study, we found that EA effectively caused cell-death in SW982 cells.…”

“…A few molecular targets for potent EA cancer cell-death have been proposed: PKCθ 2 , TRPC4/C1 or TRPC4 3 , 5 , and sphingolipids 7 . High concentration of EA (>1 μM) blocks voltage-dependent L-type Ca 2+ channels via an interaction with dihydropyridine binding sites 26 , but this effect is unlikely to be relevant to the cancer cell cytotoxic action of EA. EA-induced cancer cell-death was in part resistant to a TRPC4 inhibitor ML204 even at high concentrations (>50 μM 5 , 9 ), suggesting that EA has multiple targets.…”

Englerins: A Comprehensive Review

“…The potency of englerin A ( 1 ) in this biological system was only 6 μ M, indicating that while it may be a useful probe of the channel, it is unlikely to play a major role in the effect of englerin A on kidney cancer cells. 67 …”