What is a Pharmacological Chaperone?
Pharmacological Chaperones (PCs) are small molecules that restore the proper folding of misfolded proteins. Back to Index
How are PCs classified?
PCs are broadly categorized into two distinct types: First-generation (Orthosteric) and Second-generation (Allosteric). For clarity and consistency in classification, we have designated compounds with inhibitory effects as First-generation PCs when the binding site is not explicitly identified in the literature. Conversely, drugs that lack inhibitory effects but stabilize their targets, or those targeting non-enzymatic proteins, are classified as Second-generation PCs. Back to Index
What is a Rare Disease?
According to Orphanet, rare diseases (RD) are conditions that affect a small number of individuals compared to the general population (≤ 1 in 2,000 people in Europe). Back to Index
What is a Rare Conformational Disease?
A subset of rare diseases in which the pathogenic phenotype is associated with protein misfolding. Back to Index
What is a Protein Variant?
A modified form of a protein. In our database, we have curated pathogenic and likely pathogenic missense variants from UniProt that are associated with conformational rare diseases (RDs). Back to Index
How is the conservation score calculated?
Conservation scores were computed using the ConSurf server, which implements the Rate4Site algorithm to estimate site-specific substitution rates. In ConSurf's output, scores are normalized to have a mean of zero, such that negative values represent sites that are more conserved, while positive values correspond to sites that are less conserved relative to the overall mean of the input protein.
How is the effect of mutations on protein stability predicted?
The change in Gibbs free energy of unfolding (ΔΔG) was predicted using a consensus of three different prediction tools: MAESTRO, RaSP and ThermoMPNN. The consensus was determined by aggregating the predictions of these tools. Classification is based on sign: if at least two predictors yeld a negative ΔΔG, the variant is classified as destabilizing; conversely, if two or more values are positive, the variant is considered stabilizing. If two predictions fall into the -0.5 to 0.5 kcal/mol range, the variant is classified as neutral. If each predictor yelds a different classification, the sign of the neutral prediction is used to resolve the tie, with negative values interpreted as destabilizing and positive values as stabilizing.
What is an Efficacy Test?
Any evaluation, ranging from in vitro assays to clinical trials, assessing the susceptibility of a variant to chaperone treatment. Back to Index
What's the possible outcome of an efficacy test?
Given the heterogeneous nature of the efficacy tests, we have opted for a simple classification: amenable - the drug is effective in restoring the healthy phenotype; nonamenable - the drug shows moderate activity but is insufficient to restore the healthy phenotype; noactivity - the drug exhibits no measurable effect. Back to Index
How to use CIRCLE?
CIRCLE can be queried by Target, Chaperone, Disease, and Efficacy Test. When hovering over the "Search by" item in the navigation bar at the top-left corner of the platform, a dropdown submenu appears with clickable buttons (Target, Chaperone, Disease, Efficacy Test). Each button directs the user to the corresponding section, where searches can be performed. More detailed instructions are provided within each section. Back to Index