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Insights to ligand binding to the monoamine transporters-from homology modeling to LeuBAT and dDAT.

Koldsø H, Grouleff J, Schiøtt B - Front Pharmacol (2015)

Bottom Line: Various studies have revealed experimentally validated binding modes of numerous ligands to the BATs using homology modeling.Here we examine and discuss the similarities between the binding models of substrates, antidepressants, psychostimulants, and mazindol in homology models of the human BATs and the recently published crystal structures of the Drosophila dopamine transporter and the engineered protein, LeuBAT.The comparison reveals that careful computational modeling combined with experimental data can be utilized to predict binding of molecules to proteins that agree very well with crystal structures.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Oxford , Oxford, UK ; inSPIN and iNANO Centers, Department of Chemistry, Aarhus University , Aarhus C, Denmark.

ABSTRACT
Understanding of drug binding to the human biogenic amine transporters (BATs) is essential to explain the mechanism of action of these pharmaceuticals but more importantly to be able to develop new and improved compounds to be used in the treatment of depression or drug addiction. Until recently no high resolution structure was available of the BATs and homology modeling was a necessity. Various studies have revealed experimentally validated binding modes of numerous ligands to the BATs using homology modeling. Here we examine and discuss the similarities between the binding models of substrates, antidepressants, psychostimulants, and mazindol in homology models of the human BATs and the recently published crystal structures of the Drosophila dopamine transporter and the engineered protein, LeuBAT. The comparison reveals that careful computational modeling combined with experimental data can be utilized to predict binding of molecules to proteins that agree very well with crystal structures.

No MeSH data available.


Related in: MedlinePlus

Comparison of psychostimulants, mazindol and antidepressant binding between the dDAT and LeuBAT crystal structures and human BAT homology models. (A) Comparison of releaser binding. D-amphetamine (gray) and (+)-methamphetamine (light brown) from dDAT crystal structures (Wang et al., 2015) and PP (cyan) within a hDAT homology model (Severinsen et al., 2012). hDAT labels are shown in italic. (B) Comparison of cocaine and analogs binding. Cocaine (light gray) and RTI-55 (white) from dDAT crystal structures (Wang et al., 2015) and cocaine (yellow) within a hSERT homology model (Koldsø et al., 2013a). hSERT labels are shown in italic. (C,D) Comparison of NRI and SSRI binding. (C) Nisoxetine (gray) and reboxetine (light purple) from dDAT crystal structures (Penmatsa et al., 2015) and S-citalopram (green) within a hSERT homology model (Koldsø et al., 2010). hSERT labels are shown in italic. (D) Sertraline (light gray), R-fluoxetine (orange), paroxetine (yellow), fluvoxamine (purple) within LeuBAT crystal structures (Wang et al., 2013) and nisoxetine (blue) within dDAT (Penmatsa et al., 2015) compared to S-citalopram (green; Koldsø et al., 2010) and R-fluoxetine (brown; Andersen et al., 2014) from hSERT homology models. LeuBAT labels are shown in normal font, dDAT labels are underlined and hSERT labels are shown in italic. (E) Comparison of mazindol binding. Mazindol in LeuBAT crystal structure (white; Wang et al., 2013). Mazindol binding to a hDAT homology model (light purple) and a hSERT homology model (dark purple; Severinsen et al., 2014). hDAT labels are underlined and hSERT labels are italic. The view has been rotate 180 degrees compared to (A–D). (F) Comparison of the tricyclic antidepressant binding. Clomipramine (white) in LeuBAT crystal structure (Wang et al., 2013). Imipramine (light orange) and 3-cyano imipramine (dark orange) binding to a hSERT homology model (Sinning et al., 2010). hSERT labels are italic. The view has been rotate 180 degrees compared to (A–D).
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Figure 2: Comparison of psychostimulants, mazindol and antidepressant binding between the dDAT and LeuBAT crystal structures and human BAT homology models. (A) Comparison of releaser binding. D-amphetamine (gray) and (+)-methamphetamine (light brown) from dDAT crystal structures (Wang et al., 2015) and PP (cyan) within a hDAT homology model (Severinsen et al., 2012). hDAT labels are shown in italic. (B) Comparison of cocaine and analogs binding. Cocaine (light gray) and RTI-55 (white) from dDAT crystal structures (Wang et al., 2015) and cocaine (yellow) within a hSERT homology model (Koldsø et al., 2013a). hSERT labels are shown in italic. (C,D) Comparison of NRI and SSRI binding. (C) Nisoxetine (gray) and reboxetine (light purple) from dDAT crystal structures (Penmatsa et al., 2015) and S-citalopram (green) within a hSERT homology model (Koldsø et al., 2010). hSERT labels are shown in italic. (D) Sertraline (light gray), R-fluoxetine (orange), paroxetine (yellow), fluvoxamine (purple) within LeuBAT crystal structures (Wang et al., 2013) and nisoxetine (blue) within dDAT (Penmatsa et al., 2015) compared to S-citalopram (green; Koldsø et al., 2010) and R-fluoxetine (brown; Andersen et al., 2014) from hSERT homology models. LeuBAT labels are shown in normal font, dDAT labels are underlined and hSERT labels are shown in italic. (E) Comparison of mazindol binding. Mazindol in LeuBAT crystal structure (white; Wang et al., 2013). Mazindol binding to a hDAT homology model (light purple) and a hSERT homology model (dark purple; Severinsen et al., 2014). hDAT labels are underlined and hSERT labels are italic. The view has been rotate 180 degrees compared to (A–D). (F) Comparison of the tricyclic antidepressant binding. Clomipramine (white) in LeuBAT crystal structure (Wang et al., 2013). Imipramine (light orange) and 3-cyano imipramine (dark orange) binding to a hSERT homology model (Sinning et al., 2010). hSERT labels are italic. The view has been rotate 180 degrees compared to (A–D).

Mentions: Since drug addiction is an enormous burden to society and human health, it is extremely important to understand the molecular mechanism of how these compounds interact with the BATs. Drugs of abuse include inhibitors like cocaine and a class of compounds such as amphetamine, which are able to reverse the direction of transport in BATs by a mechanism that is still not fully understood. This class of molecules is termed “releasers” and includes amphetamine, methamphetamine and some phenyl-piperazine (PP) derived compounds. The binding of PP and an analog has been studies computationally using homology models of hDAT and hSERT (Severinsen et al., 2012). The recently published crystal structure of dDAT included structures that have D-amphetamine and (+)-methamphetamine bound (Wang et al., 2015). In Figure 2A an overlay of the two releasers from the crystal structures are displayed along with the position of PP within a hDAT model (Severinsen et al., 2012). As can be observed, there is a pronounced agreement with the position of the releasers within the S1 binding site of DAT. The orientation of PP in hDAT has been observed to be identical to the one observed within hSERT and similar to the orientation of the substrate SERT (Severinsen et al., 2012). The binding of amphetamine described by Beuming et al. (2008) additionally shows this same orientation of amphetamine to a hDAT homology model (Beuming et al., 2008). This could indicate that the substrates and releasers, which are all expected to be transported by the BATs, occupy a similar space within the central binding site and that the orientation is conserved amongst the BATs.


Insights to ligand binding to the monoamine transporters-from homology modeling to LeuBAT and dDAT.

Koldsø H, Grouleff J, Schiøtt B - Front Pharmacol (2015)

Comparison of psychostimulants, mazindol and antidepressant binding between the dDAT and LeuBAT crystal structures and human BAT homology models. (A) Comparison of releaser binding. D-amphetamine (gray) and (+)-methamphetamine (light brown) from dDAT crystal structures (Wang et al., 2015) and PP (cyan) within a hDAT homology model (Severinsen et al., 2012). hDAT labels are shown in italic. (B) Comparison of cocaine and analogs binding. Cocaine (light gray) and RTI-55 (white) from dDAT crystal structures (Wang et al., 2015) and cocaine (yellow) within a hSERT homology model (Koldsø et al., 2013a). hSERT labels are shown in italic. (C,D) Comparison of NRI and SSRI binding. (C) Nisoxetine (gray) and reboxetine (light purple) from dDAT crystal structures (Penmatsa et al., 2015) and S-citalopram (green) within a hSERT homology model (Koldsø et al., 2010). hSERT labels are shown in italic. (D) Sertraline (light gray), R-fluoxetine (orange), paroxetine (yellow), fluvoxamine (purple) within LeuBAT crystal structures (Wang et al., 2013) and nisoxetine (blue) within dDAT (Penmatsa et al., 2015) compared to S-citalopram (green; Koldsø et al., 2010) and R-fluoxetine (brown; Andersen et al., 2014) from hSERT homology models. LeuBAT labels are shown in normal font, dDAT labels are underlined and hSERT labels are shown in italic. (E) Comparison of mazindol binding. Mazindol in LeuBAT crystal structure (white; Wang et al., 2013). Mazindol binding to a hDAT homology model (light purple) and a hSERT homology model (dark purple; Severinsen et al., 2014). hDAT labels are underlined and hSERT labels are italic. The view has been rotate 180 degrees compared to (A–D). (F) Comparison of the tricyclic antidepressant binding. Clomipramine (white) in LeuBAT crystal structure (Wang et al., 2013). Imipramine (light orange) and 3-cyano imipramine (dark orange) binding to a hSERT homology model (Sinning et al., 2010). hSERT labels are italic. The view has been rotate 180 degrees compared to (A–D).
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Figure 2: Comparison of psychostimulants, mazindol and antidepressant binding between the dDAT and LeuBAT crystal structures and human BAT homology models. (A) Comparison of releaser binding. D-amphetamine (gray) and (+)-methamphetamine (light brown) from dDAT crystal structures (Wang et al., 2015) and PP (cyan) within a hDAT homology model (Severinsen et al., 2012). hDAT labels are shown in italic. (B) Comparison of cocaine and analogs binding. Cocaine (light gray) and RTI-55 (white) from dDAT crystal structures (Wang et al., 2015) and cocaine (yellow) within a hSERT homology model (Koldsø et al., 2013a). hSERT labels are shown in italic. (C,D) Comparison of NRI and SSRI binding. (C) Nisoxetine (gray) and reboxetine (light purple) from dDAT crystal structures (Penmatsa et al., 2015) and S-citalopram (green) within a hSERT homology model (Koldsø et al., 2010). hSERT labels are shown in italic. (D) Sertraline (light gray), R-fluoxetine (orange), paroxetine (yellow), fluvoxamine (purple) within LeuBAT crystal structures (Wang et al., 2013) and nisoxetine (blue) within dDAT (Penmatsa et al., 2015) compared to S-citalopram (green; Koldsø et al., 2010) and R-fluoxetine (brown; Andersen et al., 2014) from hSERT homology models. LeuBAT labels are shown in normal font, dDAT labels are underlined and hSERT labels are shown in italic. (E) Comparison of mazindol binding. Mazindol in LeuBAT crystal structure (white; Wang et al., 2013). Mazindol binding to a hDAT homology model (light purple) and a hSERT homology model (dark purple; Severinsen et al., 2014). hDAT labels are underlined and hSERT labels are italic. The view has been rotate 180 degrees compared to (A–D). (F) Comparison of the tricyclic antidepressant binding. Clomipramine (white) in LeuBAT crystal structure (Wang et al., 2013). Imipramine (light orange) and 3-cyano imipramine (dark orange) binding to a hSERT homology model (Sinning et al., 2010). hSERT labels are italic. The view has been rotate 180 degrees compared to (A–D).
Mentions: Since drug addiction is an enormous burden to society and human health, it is extremely important to understand the molecular mechanism of how these compounds interact with the BATs. Drugs of abuse include inhibitors like cocaine and a class of compounds such as amphetamine, which are able to reverse the direction of transport in BATs by a mechanism that is still not fully understood. This class of molecules is termed “releasers” and includes amphetamine, methamphetamine and some phenyl-piperazine (PP) derived compounds. The binding of PP and an analog has been studies computationally using homology models of hDAT and hSERT (Severinsen et al., 2012). The recently published crystal structure of dDAT included structures that have D-amphetamine and (+)-methamphetamine bound (Wang et al., 2015). In Figure 2A an overlay of the two releasers from the crystal structures are displayed along with the position of PP within a hDAT model (Severinsen et al., 2012). As can be observed, there is a pronounced agreement with the position of the releasers within the S1 binding site of DAT. The orientation of PP in hDAT has been observed to be identical to the one observed within hSERT and similar to the orientation of the substrate SERT (Severinsen et al., 2012). The binding of amphetamine described by Beuming et al. (2008) additionally shows this same orientation of amphetamine to a hDAT homology model (Beuming et al., 2008). This could indicate that the substrates and releasers, which are all expected to be transported by the BATs, occupy a similar space within the central binding site and that the orientation is conserved amongst the BATs.

Bottom Line: Various studies have revealed experimentally validated binding modes of numerous ligands to the BATs using homology modeling.Here we examine and discuss the similarities between the binding models of substrates, antidepressants, psychostimulants, and mazindol in homology models of the human BATs and the recently published crystal structures of the Drosophila dopamine transporter and the engineered protein, LeuBAT.The comparison reveals that careful computational modeling combined with experimental data can be utilized to predict binding of molecules to proteins that agree very well with crystal structures.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Oxford , Oxford, UK ; inSPIN and iNANO Centers, Department of Chemistry, Aarhus University , Aarhus C, Denmark.

ABSTRACT
Understanding of drug binding to the human biogenic amine transporters (BATs) is essential to explain the mechanism of action of these pharmaceuticals but more importantly to be able to develop new and improved compounds to be used in the treatment of depression or drug addiction. Until recently no high resolution structure was available of the BATs and homology modeling was a necessity. Various studies have revealed experimentally validated binding modes of numerous ligands to the BATs using homology modeling. Here we examine and discuss the similarities between the binding models of substrates, antidepressants, psychostimulants, and mazindol in homology models of the human BATs and the recently published crystal structures of the Drosophila dopamine transporter and the engineered protein, LeuBAT. The comparison reveals that careful computational modeling combined with experimental data can be utilized to predict binding of molecules to proteins that agree very well with crystal structures.

No MeSH data available.


Related in: MedlinePlus