Serotonin Receptor 1B and 2B with Sumatriptan
This Jmol Exploration was created using the Jmol Exploration Webpage Creator from the MSOE Center for BioMolecular Modeling.
A 20 year old female patient was prescribed oral sumatriptan tablets to help treat her chronic migraines. The patient had a frightening reaction upon taking the medication, where she experienced tightness in her chest and throat. The tightness continued to worsen to the point that the patient had an anxiety attack. When she sought medical help, it was determined that the adverse event she experienced was due to the sumatriptan she had been given. Upon consulting with her pharmacist and physician, the patient decided that the benefits of sumatriptan did not outweigh the side effects that she experienced.
In humans, the neurotransmitter serotonin is found in the gastrointestinal tract, the platelets, and in the central nervous system. It has many functions that are dependent on its location in the body. In the cranial arteries and veins, serotonin works to cause vasoconstriction of the blood vessels amongst other things. Migraines can be explained through genetic factors, where neurons are less able to release serotonin. This predisposes individuals to have vasodilated blood vessels, which can then cause nerves to signal for pain. With this in mind, sumatriptan was created to mimic our endogenous serotonin and is an agonist to serotonin receptors 5-HT1B and 5HT1-D. Sumatriptan ideally would bind the 5HT-1B receptor in the cranial vasculature causing vasoconstriction and correcting the problem.
Unfortunately serotonin receptors are not located solely in the brain and sumatriptan can have off target effects that are not ideal. Vasoconstriction can occur in the coronary arteries when taking triptans, leading to a feeling of tightness of chest. This adverse effect is rare, however off target effects have included other cardiovascular complications and is why so much time and effort has been put into establishing pharmacophores for the different serotonin receptors.
Before we discuss pharmacophores, lets familiarize ourselves with the protein receptor 5HT-1B. If you click the following button, you will be able to visualize the 3D structure.
Protein StructureNot only can we look at the tertiary structure, but we can also look at the secondary structure. The following button shows the many alpha helices that are present on the receptor.
Secondary StructureNow that we have familiarized ourselves with 5HT-1B, lets take a look at where a drug, Dihydroergotamine, would bind. This specific location is actually the active site, which is where a molecule can bind the receptor to activate or inhibit it.
Dihydroergotamine Shown in Green
Sumatriptan and Dihydroergotamine are Serotonin agonists within the Triptan drug class. Common pharmacophore across all three molecules is the indole ring followed by a two carbon linker connected to an amide (Figure 1). Figure 2 highlights polar and non-polar bonds between Serotonin and amino acids within receptors 5-HT1B (light blue) and 5-HT2B (black). The positively charged nitrogen of the amide forms a bond with the carboxylate of the aspartic acid (D129). The nitrogen of the indole ring forms a hydrogen bond with the threonine amino acid (T134). Non-polar interactions also occur between the benzene ring of the indole and Serine.
No crystallization of Sumatriptan bound to 5-HT1B has been created, but Dihyrdroergotamine has been crystallized. The same Serotonin pharmacophore binding can be seen with Dihydroergotamine as shown in Figure 2.
Click on the button below to view Dihydroergotamine in the binding pocket. Note that the amino acids shown in grey are those interacting with it.
Dihydroergotamine in GreenThis view, shows the binding pocket in both grey and orange. Note that the amino acids in orange interact with Dihydroergotamine hydrophobically.
Hydrophobic Interactions
Finally, the last view shows both the hydrogen bond interactions (in red) and the hydrophobic interactions (in orange). The serotonin portion of dihydroergotamine is green, where as dihydroergotamine is grey otherwise.
Hydrogen Bond and Hydrophobic Interactions
In order to create a specific 5HT-1B agonist, the structural differences between 5HT1B and 5HT1D need to be exploited. To figure out the differences between the two receptors, a BLAST search was run only to find a single amino acid difference for the binding site. There is however significant differences between the proteins in many other locations than the binding site.
Amino acid differences between the two receptors could potentially be exploited further up the sequence. Docking simulations along with the crystal structures were used to determine that a single amino acid difference, methionine (M218), is responsible for Sumatriptan having no activity in serotonin receptor 5-HT2B. M218 is able to allosterically block Sumatriptan from binding. Unfortunately, receptor 5-HT1D has not been crystallized yet. If this were done, the same docking simulations could potentially identify possible allosteric differences between 5HT1B and 5HT1D.
With all of this in mind, Sumatriptan is an anti-migraine medication that is an agonist to 5-HT1B and 5-HT1D receptors. A common adverse side effect of this medication is a tightening sensation in the face, limbs, and/or chest nicknamed the 'triptan sensation'. A randomized control trial showed that a 5-HT1D receptor agonist medication had no anti-migraine effect, yet several patients still experienced chest tightness. If a crystallized structure of 5-HT1D can be created, binding site differences between the two receptors could be explored to create a drug that is selective for just the 5-HT1B receptor. This could potentially lead to an anti-migraine drug without adverse side effects.
1. Welch K, Mathew N, Stone P, Rosamond W, Saiers J, Gutterman D. Tolerability of sumatriptan: clinical trials and post-marketing experience. Cephalalgia: An International Journal of Headache [serial online]. October 2000;20(8):687-695. Available from: MEDLINE with Full Text, Ipswich, MA. Accessed November 8, 2014.
2.Humphrey, PA. The Discovery of a New Drug Class for the Acute Treatment of Migraine. Headache: The Journal of Head and Face Pain. 2007; 47(Suppl 1): S10-S18. http://onlinelibrary.wiley.com/doi/10.1111/j.1526-4610.2007.00672.x/pdf. Aprili 2007. Accessed November 13, 2014.
3. Gomez-Mancilla B, Cutler NR, Leibowitz MT. Safety and efficacy of PNU-142633, a selective 5-HT1D agonist, in patients with acute migraine. Cephalalgia: An International Journal of Headache [serial online] 2001; 21 (7): 727-732. http://0-cep.sagepub.com.topcat.switchinc.org/content/21/7/727.full.pdf. Accessed November 13, 2014.
4. Wang C, Jiang Y, Ma J, et al. Structural Basis for Molecular Recognition at Serotonin Receptors. Science May 2013; 340 (6132): 610-614. http://www.sciencemag.org/content/340/6132/610. Accessed November 13, 2014.