A high‐quality homology model for the human dopamine transporter validated for drug design purposes

The human dopamine transporter (hDAT) plays many vital functions within the central nervous system and is thus targeted by many pharmaceutical agents. Dopamine‐related therapies are in current development for individuals with dopamine‐related disorders including depression, Parkinson's disease, and psychostimulant addictions such as cocaine abuse. Yet, most efforts to develop new dopamine therapies are within costly structure–activity relationship studies. Through structure‐based drug design techniques, the binding site of hDAT can be utilized to develop novel selective and potent dopamine therapies at reduced costs. However, no structural models of hDAT specifically validated for rational drug design purposes currently exist. Here, using the Drosophila dopamine transporter as a template, a homology model for the hDAT was developed and validated. The model was able to reproduce experimental binding modes with great accuracy, was able to rank inhibitors in the correct order of increasing potency with an R2 value of 0.81 for the test set, and it also outperformed other published hDAT models. Thus, the model can be used reliably in structure‐based drug design projects. A high‐quality model for the human dopamine transporter was specifically constructed for drug design purposes. The model was able to reproduce experimental results and was able to rank the group of test set inhibitors in the correct order.