Perturbation-theory machine learning for mood disorders: virtual design of dual inhibitors of NET and SERT proteins.

Mood disorders affect the daily lives of millions of people worldwide. The search for more efficient therapies for mood disorders remains an active field of research. In silico approaches can accelerate the search for inhibitors against protein targets related to mood disorders. Here, we developed the first model perturbation-theory machine learning model based on a multiplayer perceptron network (PTML-MLP) for the simultaneous prediction and design of virtual dual-target inhibitors against two proteins associated with mood disorders, namely norepinephrine and serotonin transporters (NET and SERT, respectively). The PTML-MLP model had an accuracy of around 80%. From a chemical point of view, the PTML-MLP model could accurately identify both single- and dual-target inhibitors present in the dataset used to build it. Through the application of the fragment-based topological design (FBTD) approach, the molecular descriptors (multi-label graph-based indices) present in the PTML-MLP model were physicochemically and structurally interpreted. Such interpretations enabled (a) the extraction of different molecular fragments with a positive influence on the enhancement of the dual-target activity and (b) the design of four new drug-like molecules by assembling (fusing and/or connecting) several suitable molecular fragments. The designed molecules were predicted by the PTML-MLP model to exhibit dual-target activity against the NET and SERT proteins. These predictions, together with the estimated druglikeness suggest that the designed molecules could be new promising chemotypes to be considered for future synthesis and biological experimentation in the context of treatments for mood disorders.