Virtual Screening for Promising Kinetic Stabilizers of Light Chains in Immunoglobulin Light Chain Amyloidosis Through Drug Repurposing

In immunoglobulin light chain amyloidosis, unstable immunoglobulin light chains aggregate as amyloid fibrils in organs, leading to organ failure and death in more than 50% of untreated patients. Research by Morgan et al. (Morgan, G. J. et. al., Proceedings of the National Academy of Sciences 2019, 116, 8360–8369) and Yan et al. (Yan, N. L. et. al., Journal of Medicinal Chemistry 2021, 64, 6273–6299) has shown that several classes of small molecules can be used as kinetic stabilizers of native light chains and potentially slow or stop the disease. Based on their criteria of a clinically successful kinetic stabilizer, this study includes an in-silico virtual screening of drugs approved by the U.S. Food and Drug Administration to find promising candidates of kinetic stabilizers through drug repurposing. Of these candidates, molecular dynamics simulations and subsequent studies of molecular mechanics with generalized Born and surface area solvation suggest that delavirdine and pazopanib can potentially be used as kinetic stabilizers of native light chains.