Ankulu Ma, Aparna.Na, Amol Shirfulea, Raju Naik Vankudavathb, Arjun .L. Khandare a
Neurolathyrism is a neurological disorder engendered by excessive consumption of Lathyrus sativus (Grass pea) comprising large amounts of the neurotoxin, �?²-N-Oxalyl-L, �?±, �?²- diaminopropionic acid (�?²-ODAP), a structural analogue of glutamate. �?²-ODAP acts by binding at AMPA (�?± -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) selective Ionotropic glutamate receptors (iGluRs), and blocking glutamate transporters in the neural milieu. This might direct a sustained increase in the concentration of both ODAP and glutamate in neuronal synapses, triggering excitotoxic degeneration of neurons. We propose that incidence of Neurolathyrism is preferably due to neuronal damage caused by high affinity binding of �?²-ODAP rather than glutamate excitotoxicity, which is usually purported in various neurodegenerative disorders. Our present in silico study using Accelrys Discovery Studio (ADS), CHARMm force field, SMART (Hybrid protocol of Steepest Descent and Conjugate Gradient Method) protocol and experimental results we obtained justify selective high affinity interaction of �?²-ODAP (dock score of 104.079) with iGluR protein [Crystal structure of iGluR2 ligand binding domain from homo sapiens (PDB ID: 3RN8)] when compared to ligands of Glutamate (dock score- 29.000), Tyrosine (dock score- 39.654). This data supports our proposition that �?²-ODAP but not glutamate binds and acts at synapse by causing intensive calcium influx and mitochondrial energy deprivation of motor neurons, ultimately leading to spastic paralysis.
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