Differentiating Physicochemical Properties between Addictive and Nonaddictive ADHD Drugs Revealed by Molecular Dynamics Simulation Studies.

Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed mental disorder of children and adolescents. Although psychostimulants are currently the first-line drugs for ADHD, their highly addictive profile raises great abuse concerns. It is known that psychostimulants' addictiveness is largely attributed to their interaction with dopamine transporter (DAT) and their binding modes in DAT can thus facilitate the understanding of the mechanism underlining drugs' addictiveness. However, no DAT residue able to discriminate ADHD drugs' addictiveness is identified, and the way how different drug structures affect their abuse liability is still elusive. In this study, multiple computational methods were integrated to differentiate binding modes between approved psychostimulants and ADHD drugs of little addictiveness. As a result, variation in energy contribution of 8 residues between addictive and nonaddictive drugs was observed, and a reduction in hydrophobicity of drugs' 2 functional groups was identified as the indicator of drugs' addictiveness. This finding agreed well with the physicochemical properties of 8 officially reported controlled substances. The identified variations in binding mode can shed light on the mechanism underlining drugs' addictiveness, which may thus facilitate the discovery of improved ADHD therapeutics with reduced addictive profile.