One way or another, many psychiatric drugs work by binding to receptor molecules in the brain that are sensitive to the neurotransmitter dopamine, a chemical signal that is central to how our experiences shape our behavior. But because scientists still don't understand the differences between the many kinds of dopamine receptors present on brain cells, most of these drugs are "messy," binding to multiple different dopamine receptor molecules and leading to serious side effects ranging from movement disorders to pathological gambling.
Now, researchers report a major step forward towards designing more powerful psychiatric drugs with fewer side effects. As reported in Science, the team has determined the crystal structure of a specific dopamine receptor called D4 at an incredibly high resolution - the highest for any dopamine, serotonin, or epinephrine (aka adrenaline) receptor to date - allowing them to design a new compound that tightly binds only to D4 and none of the other 320 receptors they tested.
Earlier this year, the same team solved the crystal structure of LSD bound to a serotonin receptor to learn why acid trips last so long and how to perhaps tweak the drug to be less potent.
The D4 dopamine receptor has been implicated in attention deficit/hyperactivity disorder (ADHD), cancer metastasis, and even erectile dysfunction. Similar dopamine receptor subtypes are crucial factors in conditions including schizophrenia, addiction, Alzheimer's disease, depression, and Parkinson's disease. However, there are currently few specific drugs for the D4 subtype that can target it and it alone, which has prevented researchers from isolating the specific function of D4 compared to other dopamine receptors. Current drugs that target dopamine receptors also cause side effects such as Parkinson's-like movement disorders.
"We now have the ability to get a crystal-clear image of these receptors to see details like never before," said co-senior author . "That's the key. Seeing these details allowed us to create a compound that tightly binds only to one kind of receptor. Our ultimate goal is to avoid so-called 'scattershot drugs' that hit many unwanted receptors and cause serious and potentially fatal side effects."
Co-senior author said, "Our computational modeling capabilities allowed us to virtually screen over 600,000 compounds much faster than traditional screening methods and create a hierarchy of compounds that potentially bind only to the D4 dopamine receptor. Our work to create better drugs is far from over, but the computer-based screening tools used here are becoming an ever-more reliable tool in our arsenal."
Dopamine receptors are part of a large family of molecules called G protein-coupled receptors, or GPCRs, which are the intended targets of approximately 35 percent of all drugs on the market. Despite their importance, very little is known about the structures of the vast majority of GPCRs, including D4 and other dopamine receptors, making it challenging to design more precise drugs with fewer side effects.
Typically, scientists have solved the chemical structure of proteins using a technique called X-ray crystallography: they cause the protein to condense into a tightly packed crystal lattice, then shoot x-rays at the crystal and can calculate the protein's structure from the resulting diffraction patterns. However, getting the D4 protein to crystallize with a drug bound to it -- in order to pinpoint the receptor's site of action -- had proved an unsolved challenge.
To solve the high-resolution structure of D4, researchers conducted a series of intense experiments over three years to get the D4 receptor to crystallize. They dissolved receptor molecules in water-based buffers and then slowly removed the water. Then, in order to be sure the receptors were sitting perfectly still so they could be imaged, authors employed a variety of experimental tricks - outlined in the Science paper - to carefully draw out water at the exact right conditions until the receptors were packed tightly into crystals that could then be bombarded with x-rays. The result was the first-ever super high-resolution image of the chemical architecture of D4 bound to the antipsychotic drug nemonapride.
Researchers evaluated all 600,000 of these chemical "puzzle pieces" to see how well they fit into the full D4 receptor. Once they had identified the top ten candidate compounds that computer modeling pointed to as likely binding partners with the D4 receptor, they experimentally tested them in the lab.
By tinkering with chemical links and ionic attractions here, adding new chemical groups there, they identified a virtual compound -- compound UCSF924 -- that computer simulations suggested could bind extremely tightly to the D4 receptor. Upon testing this compound in the lab, the molecule could bind to the D4 receptor 1000-times more powerfully than the initial virtual compounds.
D4-specific compound will help researchers understand, and one day drug, specific dopamine receptors.
The researchers now plan to test their new compound in animal models to determine exactly how it activates the D4 receptor, and how activating the D4 receptor alone alters brain function.
The team also plans to use the highly-selective UCSF924 compound to learn more details of how existing drugs work by altering specific cellular pathways inside cells.
Author added, "Whereas UCSF924 is far from a drug, it is a great probe, and we are making it openly available to the community via Sigma-Aldrich, as SML2022."
First high-resolution structure of dopamine receptor, D4
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