Design of optimised beta secretase inhibitors
2013
University of Leeds, Leeds, United Kingdom
Amyloid-beta accumulation is one of the major Alzheimer's disease pathological processes. The first step in the production of this peptide is the cleavage of amyloid precursor protein by beta-secretase. Therefore, this secretase is an attractive target for inhibition strategies to tackle the progression of the disease, avoiding the accumulation of amyloid-beta. Here, a computational approach is used to design several nonpeptide beta-secretase inhibitors based on a biphenylacetamide scaffold. A new library of optimised ligands was generated and the newly designed molecules had more than a 10-fold higher binding affinity than their scaffold, as suggested by their IC50. Afterwards, a final selection was done based on a cytotoxicity "in vitro" assay with an immortalised human cell line, which revealed that one of the newly designed compounds had minimal cellular toxicity. This study presents a methodology that can be used for the design and initial screening of optimised compounds to modulate the activity of therapeutic targets.
Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design
Colin W G Fishwick, A Peter Johnson, Nigel M Hooper
Added on: 08-16-2021
[1] https://pubs.acs.org/doi/10.1021/jm301127x[2] https://data.jrc.ec.europa.eu/dataset/a8fd26ef-b113-47ab-92ba-fd2be449c7eb
