| Structural highlights
Disease
SODC_HUMAN Defects in SOD1 are the cause of amyotrophic lateral sclerosis type 1 (ALS1) [MIM:105400. ALS1 is a familial form of amyotrophic lateral sclerosis, a neurodegenerative disorder affecting upper and lower motor neurons and resulting in fatal paralysis. Sensory abnormalities are absent. Death usually occurs within 2 to 5 years. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of cases leading to familial forms.[1] [2] [3] [4] [5] [6] [7] [8] [:][9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45]
Function
SODC_HUMAN Destroys radicals which are normally produced within the cells and which are toxic to biological systems.
Publication Abstract from PubMed
Aggregates of the antioxidant superoxide dismutase 1 (SOD1) are one of the major contributors to the pathogenesis of amyotrophic lateral sclerosis (ALS). Mutations in SOD1 lead to an unstable structure and aggregation that perturbs the balance of reactive oxygen species in cells. Oxidation damage to the solvent-exposed Trp32 also causes aggregation of SOD1. Here, the FDA-approved antipsychotic drug paliperidone is identified to interact with Trp32 of SOD1 by structure-based pharmacophore mapping and crystallographic studies. Paliperidone is used for the treatment of schizophrenia. The crystal structure of the complex with SOD1, refined to 2.1 A resolution, revealed that the ligand binds to the SOD1 beta-barrel in the beta-strand 2 and 3 regions, which are known to scaffold SOD1 fibrillation. The drug also makes substantial pi-pi interaction with Trp32. Microscale thermophoresis studies confirm significant binding affinity of the compound, suggesting that the ligand can inhibit or prevent tryptophan oxidation. Thus, the antipsychotic drug paliperidone or a derivative may avert SOD1 aggregation and can be used as a lead for ALS drug development.
Structure-based discovery of an antipsychotic drug, paliperidone, as a modulator of human superoxide dismutase 1: a potential therapeutic target in amyotrophic lateral sclerosis.,Aouti S, Padavattan S, Padmanabhan B Acta Crystallogr D Struct Biol. 2023 Jun 1;79(Pt 6):531-544. doi: , 10.1107/S2059798323003649. Epub 2023 May 19. PMID:37204819[46]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Aouti S, Padavattan S, Padmanabhan B. Structure-based discovery of an antipsychotic drug, paliperidone, as a modulator of human superoxide dismutase 1: a potential therapeutic target in amyotrophic lateral sclerosis. Acta Crystallogr D Struct Biol. 2023 Jun 1;79(Pt 6):531-544. PMID:37204819 doi:10.1107/S2059798323003649
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