Comparative binding of kaempferol and kaempferide on inhibiting the aggregate formation of mutant (G85R) SOD1 protein in familial amyotrophic lateral sclerosis: A quantum chemical and molecular mechanics study.

Abstract

Mutation in Cu/Zn superoxide dismutase (SOD1) at position 85 from glycine to arginine was found to be a prominent cause of aggregation characterized by an increased content of β-sheets in familial amyotrophic lateral sclerosis (fALS). Various literatures reported that natural polyphenols could act as a β-sheet breaker and therefore, treated as a potential therapeutics against various aggregated proteins involved in neurodegenerative disorders. Through computational perspective, molecular docking, quantum chemical studies, and discrete molecular dynamics were implemented to study the binding and structural effect of natural polyphenols, kaempferol, and kaempferide on mutant SOD1. Kaempferol exhibited significant binding and greater residual energy contribution with mutant SOD1 than kaempferide. More interestingly, kaempferol was found to reduce the β-sheet content augmenting the mutant conformational stability and flexibility relative to that of kaempferide. Hence, the inhibition of mutant SOD1 aggregation by kaempferol was explored, thereby suggesting kaempferol could act as a drug candidate for the design of the natural therapeutics against fALS. © 2018 BioFactors, 44(5):431-442, 2018.