Computational methods to assist in the discovery of pharmacological chaperones for rare diseases

Abstract

Abstract Pharmacological chaperones are chemical compounds able to bind proteins and stabilize them against denaturation and following degradation. Some pharmacological chaperones have been approved, or are under investigation, for the treatment of rare inborn errors of metabolism, caused by genetic mutations that often can destabilize the structure of the wild-type proteins expressed by that gene. Given that, for rare diseases, there is a general lack of pharmacological treatments, many expectations are poured out on this type of compounds. However, their discovery is not straightforward. In this review, we would like to focus on the computational methods that can assist and accelerate the search for these compounds, showing also examples in which these methods were successfully applied for the discovery of promising molecules belonging to this new category of pharmacologically active compounds.