Monoamine transporter structure, function, dynamics, and drug discovery: a computational perspective.
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.
Department of Chemistry and Biochemistry, Center for Computational Sciences, Duquesne University, Pittsburgh, Pennsylvania, USA.
Sankar
S
Manepalli
Christopher K
CK
Surratt
Jeffry D
JD
Madura
Tammy L
TL
Nolan
D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D003460:Crystallization; D004298:Dopamine / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D007930:Leucine / Q000378:metabolism*; D001523:Mental Disorders / Q000188:drug therapy / Q000503:physiopathology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D050479:Neurotransmitter Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism
D001426:Bacterial Proteins; D050479:Neurotransmitter Transport Proteins; D012701:Serotonin; D007930:Leucine; D004298:Dopamine; D009638:Norepinephrine