Neuroinformatics analyses reveal GABAt and SSADH as major proteins involved in anticonvulsant activity of valproic acid.
The unequivocal hypotheses about anticonvulsant activity of valproic acid (VPA) have always been a basic hurdle in designing next generation neurotherapeutics, particularly the anti-epileptic drugs. The present study reports about a comprehensive in-silico investigation into qualitative and quantitative binding of VPA and corresponding natural ligands of four major enzymes involved in neurotransmissions, namely-GABA transaminase (GABAt), α-keto glutarate dehydrogenase (α-KGDH), Succinate Semialdehyde dehydrogenase (SSADH) and Glutamate Decarboxylase (GAD), respectively. The molecular docking analyses revealed that VPA inhibits GABAt and α-KGDH through allosteric while SSADH through competitive mode of binding. There is an observed elevation in binding of glutamate over GAD in the presence of VPA. The docking inhibition constant (Ki) of VPA to all the studied enzymatic receptors were observed to be well below the therapeutic concentration of VPA in blood, except for α-KGDH, thus favouring GABAergic over glutamatergic mode of anticonvulsant activity of VPA. The report is probably the first comprehensive in-silico molecular study about VPA action.
Toxicology & Computational Biology Group, Centre for Bioinformatics, M D University, Rohtak 124 001, India.
Sakshi
S
Piplani
Dept. of Pharmaceutical Sciences, M D University, Rohtak 124 001, India.
Prabhakar Kumar
PK
Verma
Toxicology & Computational Biology Group, Centre for Bioinformatics, M D University, Rohtak 124 001, India. Electronic address: akumar.cbt.mdu@gmail.com.
Ajit
A
Kumar
D000612:4-Aminobutyrate Transaminase / Q000737:chemistry / Q000378:metabolism*; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003198:Computer Simulation; D005968:Glutamate Decarboxylase / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D008024:Ligands; D062105:Molecular Docking Simulation; D040681:Structural Homology, Protein; D050644:Succinate-Semialdehyde Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D014635:Valproic Acid / Q000737:chemistry / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D005971:Glutamates; D007656:Ketoglutaric Acids; D008024:Ligands; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D050644:Succinate-Semialdehyde Dehydrogenase; D007655:Ketoglutarate Dehydrogenase Complex; D000612:4-Aminobutyrate Transaminase; D005968:Glutamate Decarboxylase
GABA-transaminase; Glutamate decarboxylase; Molecular docking; Molecular modelling; Succinate semialdheyde dehydrogenase; α-Ketoglutarate dehydrogenase