Available online at www.ijpsdr.com International Journal of Pharmaceutical Sciences and Drug Research 2012; 4(1): 77-79 77 Research Article ISSN 0975-248X Development of Better Analogs of Valproic Acid for the Treatment of Epilepsy by CADD Manoj Kumar Mahto 1, 4* , Jaya Tripathi 2 , Divya R 3 , M. Bhaskar 4 1 Dept. of Bioinformatics (Biotechnology), Acharya Nagarjuna University, Guntur, Andhra Pradesh, India 2 Awadhesh Pratap Singh Vishwavidyalaya, Rewa, Madhya Pradesh, India 3 Dept. of Bioinformatics, Gulbarga University, Karnataka, India 4 Division of Animal Biotechnology, Dept. of Zoology, Sri Venkateswara University, Tirupati, Andhra Pradesh, India ABSTRACT Epilepsy is one of the major neurological disorders occurring due to the abnormal functioning of the various receptors and enzymes in the central nervous system. Many potentials drugs were developed in recent times which act on ion channels like sodium (Na + ), calcium (Ca 2+ ), chloride (Cl - ), and receptors like GABA receptor and enzymes like GABA transaminase. Some drugs act as enzyme, ion channel inhibitors or blockers, and some drugs as receptor agonist like barbiturates, benzodiazepines acting on GABA receptors. In the present study performed computational techniques in order to develop better inhibitors for the enzyme GABA transaminase by modifying the terminal ‘methyl’ group of the Valproic acid structure with electrophilic, nucleophile and neutral pharmacophoric features. Molecular mechanics studies has been carried out for the analogs and protein – ligand interactions of these analogs was identified through docking studies using GOLD 4.1 software against the enzyme 4-aminobutyrate-aminotransferase(GABA transaminase). From the docking studies we found that replacement of methyl with amine, hydrogen and hydroxyl groups (hydrophilic groups), are showing better fitness than that of the valproic acid. Keywords: Epilepsy, Valproic acid, GABA transaminase, molecular docking, Binding Affinity. INTRODUCTION As per the rate of the human evolution, we can observe the fastness in the new generations all because of the Neurons. Epilepsy or seizure disorder is a nervous disorder that is due to abnormal signaling by clusters of nerves in the brain, altering individual’s consciousness, actions or movements i.e. the source of the disease is brain but may affect any part of the body later. [1] There are lots of reasons for the occurrence of the diseases. Mutations in some genes are linked to few types of epilepsy. [2] Several genes that code for protein subunits of voltage-gated and ligand-gated ion channels have been associated with forms of generalized epilepsy and infantile seizure syndromes. [3] It has been found that epilepsy is bit more common in men than in women and can occur in all age groups. African- Americans are mostly affected than Caucasians. [4] Individuals with Alzheimer, mental retardation or cerebral palsy, infection (meningitis) and stroke in their history are more prone to the disease, though hormone fluctuations, *Corresponding author: Mr. Manoj Kumar Mahto, Dept. of Bioinformatics (Biotechnology), Acharya Nagarjuna University, Guntur, Andhra Pradesh, India; E-mail: manoj4bi@gmail.com stress, sleep patterns and photosensitivity also are the effective factors. [5] Certain drugs and sometimes surgery to remove abnormal brain cells can also help to control epilepsy though cannot be cured and with correct treatment approach one can live fully functional and normal life afterwards. [6] Epileptic malfunctioning of brain is due to abnormal signaling of nerves i.e. neurotransmitters. GABA (gamma amino butyric acid) is the most contributing neurotransmitter to seizures. [7] GABA is synthesized in brain by GABAergic neurons from amino acid glutamate in addition to vitamin B6 and acts by binding to certain plasma membrane’s transmembrane receptors. [8] This binding causes opening of ion channels allowing negatively charged Cl ions and positively charged K ions in and out of the cell resulting action potential. Excitation in the brain must be balanced with inhibition and GABA regulates neuronal excitability throughout the nervous system i.e. inhibitory neurotransmission. [9] In general GABA after synthesis in GABAergic neurons releases in synapses and transported into presynaptic terminals or glia cells and metabolized by GABA transaminase enzyme into succinic semialdehyde and glutamate. Here 4-aminobutyrate-aminotransferase (GABA receptor) was taken as target in the present study as GABA is able to induce relaxation, analgesia, and sleep thus