Monoamine Transporter Structure Function Dynamics and Drug Discovery: A Computational Perspective

摘要

With the breakthrough crystallization of the bacterial leucine transporter protein LeuT, the first available X-ray structure for the neurotransmitter/sodium symporter family, development of 3-D computational models is suddenly essential for structure–function studies on the plasmalemmal monoamine transporters (MATs). LeuT-based MAT models have been used to guide elucidation of substrate and inhibitor binding pockets, and molecular dynamics simulations using these models are providing insight into conformations involved in the substrate translocation cycle. With credible MAT models finally in hand, structure-based virtual screening for novel ligands is yielding lead compounds toward the development of new medications for psychostimulant dependence, attention deficit hyperactivity, depression, anxiety, schizophrenia, and other disorders associated with dopamine, norepinephrine, or serotonin dysregulation.Electronic supplementary materialThe online version of this article (doi:10.1208/s12248-012-9391-0) contains supplementary material, which is available to authorized users.