TY - JOUR
T1 - Identification of the antiepileptic racetam binding site in the synaptic vesicle protein 2A by molecular dynamics and docking simulations
AU - Correa-Basurto, José
AU - Cuevas-Hernández, Roberto I.
AU - Phillips-Farfán, Bryan V.
AU - Martínez-Archundia, Marlet
AU - Romo-Mancillas, Antonio
AU - Ramírez-Salinas, Gema L.
AU - Pérez-González, Óscar A.
AU - Trujillo-Ferrara, José
AU - Mendoza-Torreblanca, Julieta G.
N1 - Publisher Copyright:
© 2015 Correa-Basurto, Cuevas-Hernández, Phillips-Farfán, MartínezArchundia, Romo-Mancillas, Ramírez-Salinas, Pérez-González, Trujillo-Ferrara and Mendoza-Torreblanca.
PY - 2015/4/10
Y1 - 2015/4/10
N2 - Synaptic vesicle protein 2A (SV2A) is an integral membrane protein necessary for the proper function of the central nervous system and is associated to the physiopathology of epilepsy. SV2A is the molecular target of the anti-epileptic drug levetiracetam and its racetam analogs. The racetam binding site in SV2A and the non-covalent interactions between racetams and SV2A are currently unknown; therefore, anin silico study was performed to explore these issues. Since SV2A has not been structurally characterized with X-ray crystallography or nuclear magnetic resonance, a three-dimensional (3D) model was built. The model was refined by performing a molecular dynamics simulation (MDS) and the interactions of SV2A with the racetams were determined by docking studies. A reliable 3D model of SV2A was obtained; it reached structural equilibrium during the last 15 ns of the MDS (50 ns) with remaining structural motions in the N-terminus and long cytoplasmic loop. The docking studies revealed that hydrophobic interactions and hydrogen bonds participate importantly in ligand recognition within the binding site. Residues T456, S665, W666, D670 and L689 were important for racetam binding within the trans-membrane hydrophilic core of SV2A. Identifying the racetam binding site within SV2A should facilitate the synthesis of suitable radio-ligands to study treatment response and possibly epilepsy progression.
AB - Synaptic vesicle protein 2A (SV2A) is an integral membrane protein necessary for the proper function of the central nervous system and is associated to the physiopathology of epilepsy. SV2A is the molecular target of the anti-epileptic drug levetiracetam and its racetam analogs. The racetam binding site in SV2A and the non-covalent interactions between racetams and SV2A are currently unknown; therefore, anin silico study was performed to explore these issues. Since SV2A has not been structurally characterized with X-ray crystallography or nuclear magnetic resonance, a three-dimensional (3D) model was built. The model was refined by performing a molecular dynamics simulation (MDS) and the interactions of SV2A with the racetams were determined by docking studies. A reliable 3D model of SV2A was obtained; it reached structural equilibrium during the last 15 ns of the MDS (50 ns) with remaining structural motions in the N-terminus and long cytoplasmic loop. The docking studies revealed that hydrophobic interactions and hydrogen bonds participate importantly in ligand recognition within the binding site. Residues T456, S665, W666, D670 and L689 were important for racetam binding within the trans-membrane hydrophilic core of SV2A. Identifying the racetam binding site within SV2A should facilitate the synthesis of suitable radio-ligands to study treatment response and possibly epilepsy progression.
KW - Brivaracetam
KW - Epilepsy
KW - Levetiracetam
KW - SV2A
KW - Seletracetam
UR - http://www.scopus.com/inward/record.url?scp=84927651840&partnerID=8YFLogxK
U2 - 10.3389/fncel.2015.00125
DO - 10.3389/fncel.2015.00125
M3 - Artículo
C2 - 25914622
SN - 1662-5102
VL - 9
JO - Frontiers in Cellular Neuroscience
JF - Frontiers in Cellular Neuroscience
IS - APR
M1 - A125
ER -