Restoring adapter protein complex 4 function with small molecules: an in silico approach to spastic paraplegia 50

Abstract

This study focuses on spastic paraplegia type 50 (SPG50), an adapter protein complex 4 deficiency syndrome caused by mutations in the adapter protein complex 4 subunit mu-1 (AP4M1) gene, and on the downstream alterations of the AP4M1 protein. We applied a battery of heterogeneous computational resources, encompassing two in-house tools described here for the first time, to (a) assess the druggability potential of AP4M1, (b) characterize SPG50-associated mutations and their 3D scenario, (c) identify mutation-tailored drug candidates for SPG50, and (d) elucidate their mechanisms of action by means of structural considerations on homology models of the adapter protein complex 4 core. Altogether, the collected results indicate R367Q as the mutation with the most promising potential of being corrected by small-molecule drugs, and the flavonoid rutin as best candidate for this purpose. Rutin shows promise in rescuing the interaction between the AP4M1 and adapter protein complex subunit beta-1 (AP4B1) subunits by means of a glue-like mode of action. Overall, this approach offers a framework that could be systematically applied to the investigation of mutation-wise molecular mechanisms in different hereditary spastic paraplegias, too.

Keywords: AP4M1; AP‐4; SPG50; drug repurposing; druggability; hereditary spastic paraplegia; ligandability; molecular modeling; personalized medicine; rare diseases.