free-binding energies and molecular interac3ons of

Free-bindingenergiesandmolecularinterac3onsofyessotoxininthevoltage-gatedsodiumchannelNaV1.5:aninsilicoapproach

Several marine dinoflagellates produce unique secondary metabolites with intriguing biological ac3vi3es.Yessotoxin (YTX) and analogs are produced by three species ofmarine dinoflagellates, with potent ion-channelac3vity.ThisstudyaimedtoevaluatetheaffinityofYTXfortheNaV1.5channel,usinginsilicomodellingtools.

INTRODUCTION

Significant interac3ons and low binding free energies (ΔG), between-6.79and-10.32Kcalmol-1forYTXintheNaV1.5proteinmodel.Certainaminoacid residues inDomains I and IIwere reached, indica3ng thatthistoxinisapoten3alNaV1.5modulator.

MATERIALSANDMETHODS

AlignmentSelec3onCoverage

UniProtQ14524

HomosapiensSequencesearch

Swissmodelh]ps://

swissmodel.expasy.org/

Homologymodeling

Basicandtheoricalstructure

Primarychannelstructure

Func3onalvalida3on

Modelrefinement

Structuralvalida3on

Characteriza3on&valida3on

MolecularDocking

Blinddocking

126x126x126ÅBindingfree

energy

AutoDockToolsTriplicates

Dataanalysis

AutoDockTools1.5.6

Conforma3ons Interac3ons

Region1Region2

Region3Region4

Region5

This study cons3tutes the first approach to in silico explora3on ofpolyke3de-derived dinoflagellate toxins in pursuit of evalua3ng theirtherapeu3cpoten3al.

-15

-10

-5

0Region1 Region2 Region3 Region4 Region5

Bind

ingfreeene

rgy

(ΔGKcal·m

ol-1)

Simula5onregions

010203040

Region1 Region2 Region3 Region4 Region5

%cluster

Interaction of YTX in DI and DII of NaV1.5. YTX (pink) and different amino acids (blue)

AverageΔG=-10.3Kcalmol-1

RESULTS

What’snext?Tounderstand theeffectsofYTXon thevoltage-gatedsodium channel different studies are needed, i.e. electrophysiologyandmoleculardynamicsanalyses

Thanksto:

MaríadelCarmenOsorio-Ramírez1,LorenaMaríaDurán-Riveroll2,3,AllanD.Cembella3,andJoséCorrea-Basurto11LaboratoriodeDiseñoyDesarrollodeNuevosFármacoseInnovaciónBiotecnológica,SeccióndeEstudiosdePosgradoeInves3gación.EscuelaSuperiordeMedicina,Ins3tutoPolitécnicoNacional,CiudaddeMéxico,México;2CONACyT-DepartamentodeBiotecnologíaMarina,CentrodeInves3gaciónCientficaydeEducaciónSuperiordeEnsenada,BajaCalifornia,México;3Alfred-Wegener-Ins3tut,Helmholtz-ZentrumfürPolar-undMeeresforschung,Bremerhaven,Germany