TY - JOUR
T1 - Docking simulation of the binding interactions of saxitoxin analogs produced by the marine dinoflagellate Gymnodinium catenatum to the voltage-gated sodium channel Nav1.4
AU - Durán-Riveroll, Lorena M.
AU - Cembella, Allan D.
AU - Band-Schmidt, Christine J.
AU - Bustillos-Guzmán, José J.
AU - Correa-Basurto, José
N1 - Publisher Copyright:
© 2016 by the authors; licensee MDPI, Basel, Switzerland.
PY - 2016/5/6
Y1 - 2016/5/6
N2 - Saxitoxin (STX) and its analogs are paralytic alkaloid neurotoxins that block the voltage-gated sodium channel pore (Nav), impeding passage of Na+ ions into the intracellular space, and thereby preventing the action potential in the peripheral nervous system and skeletal muscle. The marine dinoflagellate Gymnodinium catenatum produces an array of such toxins, including the recently discovered benzoyl analogs, for which the mammalian toxicities are essentially unknown. We subjected STX and its analogs to a theoretical docking simulation based upon two alternative tri-dimensional models of the Nav1.4 to find a relationship between the binding properties and the known mammalian toxicity of selected STX analogs. We inferred hypothetical toxicities for the benzoyl analogs from the modeled values. We demonstrate that these toxins exhibit different binding modes with similar free binding energies and that these alternative binding modes are equally probable. We propose that the principal binding that governs ligand recognition is mediated by electrostatic interactions. Our simulation constitutes the first in silico modeling study on benzoyl-type paralytic toxins and provides an approach towards a better understanding of the mode of action of STX and its analogs.
AB - Saxitoxin (STX) and its analogs are paralytic alkaloid neurotoxins that block the voltage-gated sodium channel pore (Nav), impeding passage of Na+ ions into the intracellular space, and thereby preventing the action potential in the peripheral nervous system and skeletal muscle. The marine dinoflagellate Gymnodinium catenatum produces an array of such toxins, including the recently discovered benzoyl analogs, for which the mammalian toxicities are essentially unknown. We subjected STX and its analogs to a theoretical docking simulation based upon two alternative tri-dimensional models of the Nav1.4 to find a relationship between the binding properties and the known mammalian toxicity of selected STX analogs. We inferred hypothetical toxicities for the benzoyl analogs from the modeled values. We demonstrate that these toxins exhibit different binding modes with similar free binding energies and that these alternative binding modes are equally probable. We propose that the principal binding that governs ligand recognition is mediated by electrostatic interactions. Our simulation constitutes the first in silico modeling study on benzoyl-type paralytic toxins and provides an approach towards a better understanding of the mode of action of STX and its analogs.
KW - Benzoyl saxitoxin analogs
KW - Binding affinity
KW - Molecular docking
KW - Voltage-gated sodium channel
UR - http://www.scopus.com/inward/record.url?scp=84968543853&partnerID=8YFLogxK
U2 - 10.3390/toxins8050129
DO - 10.3390/toxins8050129
M3 - Artículo
C2 - 27164145
SN - 2072-6651
VL - 8
JO - Toxins
JF - Toxins
IS - 5
M1 - 129
ER -