Rational discovery of a SOD1 tryptophan oxidation inhibitor with therapeutic potential for amyotrophic lateral sclerosis |
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| Authors: | Ramu Manjula Sruthi Unni Gareth S. A. Wright Srinivas Bharath M. M. |
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| Affiliation: | 1. Department of Biophysics, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India;2. Molecular Biophysics Group, Institute of Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK;3. Department of Neurochemistry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India;4. Neurotoxicology Laboratory, Neurobiology Research Center, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India |
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| Abstract: | AbstractFormation of Cu, Zn superoxide dismutase 1 (SOD1) protein inclusions within motor neurons is one of the principal characteristics of SOD1-related amyotrophic lateral sclerosis (ALS). A hypothesis as to the nature of SOD1 aggregation implicates oxidative damage to a solvent-exposed tryptophan as causative. Here, we chart the discovery of a phenanthridinone based compound (Lig9) from the NCI Diversity Set III by rational methods by in silico screening and crystallographic validation. The crystal structure of the complex with SOD1, refined to 2.5 Å, revealed that Lig9 binds the SOD1 β-barrel in the β-strand 2 and 3 region which is known to scaffold SOD1 fibrillation. The phenanthridinone moiety makes a substantial π–π interaction with Trp32 of SOD1. The compound possesses a significant binding affinity for SOD1 and inhibits oxidation of Trp32; a critical residue for SOD1 aggregation. Thus, Lig9 is a good candidate from which to develop a new library of SOD1 aggregation inhibitors through protection of Trp32 oxidation.Communicated by Ramaswamy H. Sarma |
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| Keywords: | ALS SOD1 Trp oxidation modulators NCI diversity set virtual screening phenanthridinone derivative crystal structure binding assay |
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