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Molecular mechanism of serotonin transporter inhibition elucidated by a new flexible docking protocol.

ABSTRACT: The two main groups of antidepressant drugs, the tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitors (SSRIs), as well as several other compounds, act by inhibiting the serotonin transporter (SERT). However, the binding mode and molecular mechanism of inhibition in SERT are not fully understood. In this study, five classes of SERT inhibitors were docked into an outward-facing SERT homology model using a new 4D ensemble docking protocol. Unlike other docking protocols, where protein flexibility is not considered or is highly dependent on the ligand structure, flexibility was here obtained by side chain sampling of the amino acids of the binding pocket using biased probability Monte Carlo (BPMC) prior to docking. This resulted in the generation of multiple binding pocket conformations that the ligands were docked into. The docking results showed that the inhibitors were stacked between the aromatic amino acids of the extracellular gate (Y176, F335) presumably preventing its closure. The inhibitors interacted with amino acids in both the putative substrate binding site and more extracellular regions of the protein. A general structure-docking-based pharmacophore model was generated to explain binding of all studied classes of SERT inhibitors. Docking of a test set of actives and decoys furthermore showed that the outward-facing ensemble SERT homology model consistently and selectively scored the majority of active compounds above decoys, which indicates its usefulness in virtual screening.

SUBMITTER: Gabrielsen M

PROVIDER: S-EPMC3357065 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Molecular mechanism of serotonin transporter inhibition elucidated by a new flexible docking protocol.

Gabrielsen Mari M Kurczab Rafał R Ravna Aina W AW Kufareva Irina I Abagyan Ruben R Chilmonczyk Zdzisław Z Bojarski Andrzej J AJ Sylte Ingebrigt I

European journal of medicinal chemistry 20111020 1

The two main groups of antidepressant drugs, the tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitors (SSRIs), as well as several other compounds, act by inhibiting the serotonin transporter (SERT). However, the binding mode and molecular mechanism of inhibition in SERT are not fully understood. In this study, five classes of SERT inhibitors were docked into an outward-facing SERT homology model using a new 4D ensemble docking protocol. Unlike other docking protocols, ...[more]

PMID: 22071255

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Project description:BACKGROUND: Cathepsin B (catB) is a promising target for anti-cancer drug design due to its implication in several steps of tumorigenesis. catB activity and inhibition are pH-dependent, making it difficult to identify efficient inhibitor candidates for clinical trials. In addition it is known that heparin binding stabilizes the enzyme in alkaline conditions. However, the molecular mechanism of stabilization is not well understood, indicating the need for more detailed structural and dynamic studies in order to clarify the influence of pH and heparin binding on catB stability. RESULTS: Our pKa calculations of catB titratable residues revealed distinct protonation states under different pH conditions for six key residues, of which four lie in the crucial interdomain interface. This implies changes in the overall charge distribution at the catB surface, as revealed by calculation of the electrostatic potential. We identified two basic surface regions as possible heparin binding sites, which were confirmed by docking calculations. Molecular dynamics (MD) of both apo catB and catB-heparin complexes were performed using protonation states for catB residues corresponding to the relevant acidic or alkaline conditions. The MD of apo catB at pH 5.5 was very stable, and presented the highest number and occupancy of hydrogen bonds within the inter-domain interface. In contrast, under alkaline conditions the enzyme's overall flexibility was increased: interactions between active site residues were lost, helical content decreased, and domain separation was observed as well as high-amplitude motions of the occluding loop - a main target of drug design studies. Essential dynamics analysis revealed that heparin binding modulates large amplitude motions promoting rearrangement of contacts between catB domains, thus favoring the maintenance of helical content as well as active site stability. CONCLUSIONS: The results of our study contribute to unraveling the molecular events involved in catB inactivation in alkaline pH, highlighting the fact that protonation changes of few residues can alter the overall dynamics of an enzyme. Moreover, we propose an allosteric role for heparin in the regulation of catB stability in such a manner that the restriction of enzyme flexibility would allow the establishment of stronger contacts and thus the maintenance of overall structure.

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Molecular mechanism of serotonin transporter inhibition elucidated by a new flexible docking protocol.

Publications

Molecular mechanism of serotonin transporter inhibition elucidated by a new flexible docking protocol.

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