Two novel carprofen analogs designed via CADD show enhanced affinity for Aβ1-42 fibrils and in vitro safety.

Current treatments for Alzheimer's disease (AD) primarily manage symptoms, with no cure or effective disease-modifying therapies. A key pathological hallmark of AD is the accumulation of amyloid beta (Aβ) plaques, particularly the Aβ1-42 isoform, which is implicated in neurotoxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown promise in reducing Aβ levels and improving cognition in preclinical AD models, but their systemic side effects limit long-term use. This research aims to leverage computer-aided drug design (CADD) to develop safer and more potent NSAID derivatives specifically targeting Aβ1-42 aggregation.

Researchers employed computer-aided drug design (CADD), utilizing both structure-based and ligand-based virtual screening, to identify NSAIDs with high affinity for amyloid Aβ1-42 fibrils (PDB 2BEG). After identifying carprofen as a lead, twenty derivatives were designed through bioisosteric modifications. Two promising carprofen analogs, compound A-1 and compound A-2, were then successfully synthesized. Their predicted IC50 values and interaction energies with Aβ1-42 fibrils were calculated. Safety evaluations were conducted in vitro using L929 cells, assessing viability at concentrations up to 40 µM to determine potential cytotoxicity.

The CADD approach successfully identified carprofen as an NSAID with high predicted affinity for Aβ1-42 fibrils. Following bioisosteric modifications, two carprofen analogs (A-1 and A-2) were synthesized with high success rates: 75% for compound A-1 and 70% for compound A-2. These novel analogs demonstrated significantly improved binding properties compared to the parent compound. Their predicted IC50 values were notably lower, with a value of 1.57 µM for the most potent analog. Interaction energies with Aβ1-42 fibrils were also more favorable, recorded at -6.43 kcal/mol for A-1 and -6.67 kcal/mol for A-2, indicating stronger binding. Importantly, in vitro safety evaluations in L929 cells confirmed that both compound A-1 and compound A-2 were safe at concentrations up to 40 µM, showing no significant cytotoxicity. This suggests a favorable therapeutic window for further investigation.

The synthesized carprofen analogs exhibited lower predicted IC50 values (1.57 µM) and more negative interaction energies (-6.43 and -6.67 kcal/mol) compared to carprofen, alongside safety at 40 µM in L929 cells.