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Abstract
The study of binding site similarities can be relevant to understand the interaction of different drugs at several molecular targets. The increasing availability of protein crystal structures and the development of novel algorithms designed to evaluate three-dimensional similarities, represent a great opportunity to explore the existence of electronic and shape features shared by clinically relevant proteins, which could assist drug design and discovery. Proteins involved in the recognition of monoaminergic neurotransmitters, such as monoamine transporters or monoamine oxidases (MAO) have been related to several psychiatric and neurological disorders such as depression or Parkinson’s disease. In this work, we evaluated the possible existence of similarities among the binding sites of the serotonin transporter (SERT), the dopamine transporter (DAT), MAO-A and MAO-B. This study was carried out using molecular simulation methodologies linked to the statistical algorithm PocketMatch, which was modified in order to obtain similarities profiles. Our results show that DAT and SERT exhibit a high degree of 3-D similarities all along the pathway that is presumably involved in the substrate transport process. Distinct differences, on the other hand, were found both at the extracellular and the intracellular ends of the transporters, which might be involved in the selective initial recognition of the corresponding substrate. Similarities were also found between the active (catalytic) site of MAO-A and the extracellular vestibule of SERT (the S2 binding site). These results suggest some degree of structural convergence for these proteins, which have different functions, tissue distribution and genetic origin, but which share the same endogenous ligand (serotonin). Beyond the functional implications, these findings are valuable for the design of both selective and non-selective ligands.
Highlights
Monoaminergic neurotransmitters exert their actions by interacting with diverse protein targets in their synapses
In the present work we evaluated the likely existence of similarities among the binding sites of serotonin transporter (SERT), dopamine transporter (DAT), monoamine oxidases (MAO)-A and MAO-B
DAT and SERT share almost 70% of their amino acids sequences and their secondary and tertiary structures are relatively similar (RMSD = 3.0 Å; Figure G in S1 File) our partial 3D comparisons yielded, in many cases, PMScore values higher than 0.5, which are indicative of similarity
Summary
Monoaminergic neurotransmitters exert their actions by interacting with diverse protein targets in their synapses. Serotonin (5-HT), norepinephrine (NE) and dopamine (DA), activate either metabotropic or ionotropic receptors (e.g. β-adrenoceptors or 5-HT3 receptors, respectively), are catabolized by monoamine oxidase and/or catechol-ο-methyltransferase (in the case of NE and DA) and are pumped back into their synaptic terminals by selective transporter proteins These neurotransmitters are accumulated into synaptic vesicles inside the nerve terminals by specific transporters, and even within noradrenergic neurons the presence of the enzyme DA-β-hydroxylase can be considered as an additional site for the interaction of DA [1,2]. A central binding site is located approximately halfway across the membrane bilayer At this site, both substrates and inhibitors [10,11,12], establish an ionic interaction between the ligand amino group and the carboxylate of a conserved aspartate (D46 in DAT from Drosophila, D98 and D79 in human SERT, and DAT, respectively). Beyond the mechanistic or functional clustering implications, we anticipate that the study of binding site similarities (and differences) among these proteins can be insightful for the rational design of selectively and non-selectively acting compounds
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