This CRCNS grant application proposes structure, function, and dynamic studies on the plasma membrane dopamine (DAT) and serotonin transporters (SERT). Recently, the arduous process of identifying DAT and SERT substrate and inhibitor binding sites received an unexpected boost with the crystallization of the homologous LeuTAa leucine transporter. This crystal structure revealed hinged regions of transmembranes (TMs) 1 and 6 adjacent to the leucine substrate, with TMs 3, 8 and 10 also delineating the binding pocket. Through comparative molecular modeling techniques we have published a three-dimensional model of DAT using LeuTAa. The modeling also suggests novel inhibitor binding sites, nonidentical to dopamine, that can be tested via molecular pharmacological techniques. This project brings together a unique team of computational scientists, medicinal chemists, and pharmacologists to examine the structure, function, and dynamics of monoamine neurotransporters (MATs). The overall goal of this project is to determine binding locations for psychostimulant and antidepressant inhibitors of neurotransmitter transport, and the conformational states involved in the transport mechanism. State-of-the-art computational techniques in areas of docking, advanced molecular dynamics simulations, QSAR and structure-based design will be used to identify important residues and regions of the transporter to perform mutagenesis experiments as well as direct the synthesis of novel compounds that inhibit binding of non-neurotransmitter molecules yet retain transporter activity. In summary, this proposal (1) includes collaborations between computational and/or modeling experts (Madura research group), experimental neuropharmacoiogists (Surratt research group) and medicinal chemists (Lapinsky research group);(2) involves intense, dynamic interactions among these research groups in the model development and refinement of neurotransporters;and (3) leads to the development and testing of new models that provide a framework for the design of experiments and the generation of new hypotheses to reveal mechanisms underlying normal nervous system disease states.
The proposed studies seek to provide details illustrating how neurotransporters (DAT and SERT) interacts with its CNS-active inhibitors. Findings of this nature open the door to rational design of therapeutics for DAT and SERT-related conditions that include substance abuse and addiction (e.g. cocaine and methylphenidate), depression, anxiety disorders, attention deficit hyperactivity, narcolepsy, chronic pain and Parkinson's disease.
|Punihaole, David; Jakubek, Ryan S; Workman, Riley J et al. (2017) Monomeric Polyglutamine Structures That Evolve into Fibrils. J Phys Chem B 121:5953-5967|
|Jean, Bernandie; Surratt, Christopher K; Madura, Jeffry D (2017) Molecular dynamics of conformation-specific dopamine transporter-inhibitor complexes. J Mol Graph Model 76:143-151|
|Punihaole, David; Workman, Riley J; Hong, Zhenmin et al. (2016) Polyglutamine Fibrils: New Insights into Antiparallel ?-Sheet Conformational Preference and Side Chain Structure. J Phys Chem B 120:3012-26|
|Talbot, Jeffery N; Geffert, Laura M; Jorvig, Jessica E et al. (2016) Rapid and sustained antidepressant properties of an NMDA antagonist/monoamine reuptake inhibitor identified via transporter-based virtual screening. Pharmacol Biochem Behav 150-151:22-30|
|Asciutto, Eliana K; Gedeon, Patrick C; General, Ignacio J et al. (2016) Structure and Dynamics Study of LeuT Using the Markov State Model and Perturbation Response Scanning Reveals Distinct Ion Induced Conformational States. J Phys Chem B 120:8361-8|
|Hong, Weimin C; Kopajtic, Theresa A; Xu, Lifen et al. (2016) 2-Substituted 3?-Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations. J Pharmacol Exp Ther 356:624-34|
|Thomas, James R; Gedeon, Patrick C; Madura, Jeffry D (2014) Structural dynamics of the monoamine transporter homolog LeuT from accelerated conformational sampling and channel analysis. Proteins 82:2289-302|
|Nolan, Tammy L; Geffert, Laura M; Kolber, Benedict J et al. (2014) Discovery of novel-scaffold monoamine transporter ligands via in silico screening with the S1 pocket of the serotonin transporter. ACS Chem Neurosci 5:784-92|
|Immadisetty, Kalyan; Geffert, Laura M; Surratt, Christopher K et al. (2013) New design strategies for antidepressant drugs. Expert Opin Drug Discov 8:1399-414|
|Immadisetty, Kalyan; Madura, Jeffry D (2013) A review of monoamine transporter-ligand interactions. Curr Comput Aided Drug Des 9:556-68|
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