It is important to know exactly what their goals are when scientists develop new molecules, whether for agriculture, species control or life-saving drugs. A thorough understanding of molecules’ interactions, whether intention or accident, is crucial to ensuring their safety and effectiveness.
The cone snail toxin, known to affect insects and fish, inspired scientists at Weizmann Academy to develop a new way to find molecular targets. By combining artificial intelligence with traditional research methods, they created a pipeline that predicts which proteins are naturally affected by toxins, and their impact on ecological research and drug development. This work will be held at the 69th Annual Meeting of the Biophysics Association in Los Angeles from February 15 to 19, 2025.
Dr. Izhar Karbat and scientists from the Weizmann Institute in Israel, and Dr. Eitan Reuveny, both wanted to figure out how cone snail toxin, Concors-S1 (CS1), affects the fish, which is the prey of cone snails. CS1 is a toxin known to block potassium channels (a portal for single cells’ function) and has effective effects on fruit flies and other insects, but not mammals or other organisms (such as molluscs). But it is the targets in fish that are still elusive.
“Three years ago, we tried the best tools to find the targets of Concuni toxin, and we failed because these tools weren’t good enough. Then, there was a huge revolution in structural biology powered by artificial intelligence, ” said Carbart. In their latest attempt, he and Reuveny used two supportive calculation methods to identify the fish potassium channels that are most vulnerable to CS1 attacks.
First, they used Alphafold, a powerful AI program, to predict how toxins bind to different fish potassium channels. They then developed a new AI model, ET3, which analyzes how water molecules move around these channels. ET3 was trained to identify the irregularities in the movement of the “selective filter” around the water molecules, part of the channel through which the control ions can pass. Prevent this filter from essentially closing the channel.
By analyzing a wide range of fish potassium channels using ET3, far beyond the possibility of previous methods, they were able to identify specific channels targeted by CS1 and how to prevent them from functioning correctly. Basically, if the potassium channel is like a miniature gate that controls the flow of incoming and outgoing cells, CS1 acts like a lock that blocks these gates.
“Using molecular dynamics and new AI-driven structural tools, we were able to find a small subset of channels in fish that combine with our toxins with high affinity and could be the real targets for cone snails,” Karbart said.
“This new pipeline offers exciting opportunities and future prospects through ecological research to study actual chemical interactions in actual ecosystems,” Karbart said. He added that it could also be used in drug development, too , to identify targets according to the structure of the drug, or to determine potential off-target interactions.
For example, Karbat said: “If you develop a drug that activates channels in the human brain, you don’t want the same drug to affect channels in the human heart and cause a heart attack.”
“The power of this pipeline is that we can focus on the target or any molecule we are interested in and find a match for it,” Reuveny said.
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