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Rational design of linear tripeptides against the aggregation of human mutant SOD1 protein causing amyotrophic lateral sclerosis
Srinivasan E,
Published in Elsevier BV
PMID: 31422280
Volume: 405
Formation of protein aggregation is considered a hallmark feature of various neurological diseases. Amyotrophic lateral sclerosis is one such devastating neurodegenerative disorder characterized by mutation in Cu/Zn superoxide dismutase protein (SOD1). In our study, we contemplated the most aggregated and pathogenic mutant A4V in a viewpoint of finding a therapeutic regime by inhibiting the formation of the aggregates with the aid of tripeptides since new perspectives in the field of drug design in the current era are being focused on peptide-based drugs. Reports from the experimental study have stipulated that the SOD1 derived peptide, “LSGDHCIIGRTLVVHEKADD” was found to have the inhibitory activity against aggregated SOD1 protein. Moreover, it was determined that the hexapeptide, “LSGDHC” was the key factor in inhibiting the aggregates of SOD1. Accordingly, we utilized the computerized algorithms and programs on determining the binding efficiency and inhibitory activity of hexapeptide on mutant SOD1. Following that, we incorporated a cutting-edge methodology with the use of molecular docking, affinity predictions, alanine scanning, steered molecular dynamics (SMD) and discrete molecular dynamics (DMD) in designing the de novo tripeptides, which could act against the aggregated mutant SOD1 protein. Upon examining the results from the various conformational studies, we identified that CGH had an enhanced binding affinity and inhibitory activity against the aggregated mutant SOD1 protein than other tripeptides and hexapeptide. Thus, our study could be a lead for state-of-the-art design in peptide-based drugs for doctoring the cureless ALS disorder. © 2019 Elsevier B.V.
About the journal
JournalData powered by TypesetJournal of the Neurological Sciences
PublisherData powered by TypesetElsevier BV
Open AccessNo