In silico screening of GABA aminotransferase inhibitors from the constituents of Valeriana officinalis by molecular dock
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ORIGINAL PAPER
In silico screening of GABA aminotransferase inhibitors from the constituents of Valeriana officinalis by molecular docking and molecular dynamics simulation study Jin-Young Park 1 & Yuno Lee 2 & Hee Jae Lee 1 & Yong-Soo Kwon 3 & Wanjoo Chun 1 Received: 5 May 2020 / Accepted: 30 July 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Modulation of γ-aminobutyric acid (GABA) levels has been required in various disorders. GABA itself cannot be directly introduced into central nervous system (CNS) because of the blood brain barrier; inhibition of GABA aminotransferase (GABA-AT), which degrades GABA in CNS, has been the target for the modulation of GABA levels in CNS. Given that root extract of valerian (Valeriana officinalis) has been used for millennia as anti-anxiolytic and sedative, in silico approach was carried out to investigate valerian compounds exhibiting GABA-AT inhibiting activity. The 3D structure of human GABA-AT was created from pig crystal structure via homology modeling. Inhibition of GABA-AT by 18 valerian compounds was analyzed using molecular docking and molecular dynamics simulations and compared with known GABA-AT inhibitors such as vigabatrin and valproic acid. Isovaleric acid and didrovaltrate exhibited GABA-AT inhibiting activity in computational analysis, albeit less potent compared with vigabatrin. However, multiple compounds with low activity may have additive effects when the total extract of valeriana root was used in traditional usage. In addition, isovaleric acid shares similar backbone structure to GABA, suggesting that isovaleric acid might be a valuable starting structure for the development of more efficient GABA-AT inhibitors for disorders related with low level of GABA in the CNS. Keywords GABA aminotransferase (GABA-AT) . Valerian (Valeriana officinalis) . Homology modeling . Molecular docking . Molecular dynamics
Introduction γ-Aminobutyric acid (GABA) is the most widely distributed inhibitory neurotransmitters in central nervous system (CNS) [1]. GABA is synthesized from L-glutamate to GABA via Lglutamic acid decarboxylase and degraded through the action of GABA aminotransferase (GABA-AT, 4-aminobutyrate aminotransferase) [2]. A reduction in the concentration of GABA has been implicated in many neurological disorders such as epilepsy [3], Huntington’s disease [4], Parkinson’s * Wanjoo Chun [email protected] 1
Department of Pharmacology, College of Medicine, Kangwon National University, Hyoja-2, Chuncheon, Kangwon 200-701, South Korea
2
Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea
3
College of Pharmacy, Kangwon National University, Chuncheon 200-701, South Korea
disease [5], Alzheimer’s disease [6], and dyskinesia [7]. Inhibition of GABA-mediated inhibitory neurotransmission has been reported to play a critical role in the pathogenesis of epilepsy [3]. Selective neuronal death of striatal GABAergic neurons is the characteristic pathological feature of Huntington’s disease [4]. Va
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