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Revolutionizing Molecular Target Identification: Insights from Cone Snail Toxin Research
Understanding the interactions of newly developed molecules is essential in fields ranging from agriculture to pharmacology. Identifying the precise targets of these molecules, including both their intended and unintended effects, is crucial to assess their safety and effectiveness.
Researchers at the Weizmann Institute of Science have turned to the cone snail toxin, Conkunitzin-S1 (Cs1), for innovative methodologies in target identification. By integrating artificial intelligence with traditional research practices, the team established a workflow capable of predicting which proteins are influenced by natural toxins, offering significant applications for ecological studies and drug development.
This groundbreaking research was showcased at the 69th Biophysical Society Annual Meeting, hosted in Los Angeles from February 15 to 19, 2025.
Dr. Izhar Karbat and Dr. Eitan Reuveny, both associated with the Weizmann Institute, aimed to explore the effects of the cone snail toxin on fish, which are natural prey for these snails. Cs1 is recognized for its ability to obstruct potassium channels—vital components for cellular processes. While it exhibits strong effects on insects, including fruit flies, it does not affect mammals or other species like mollusks. Nonetheless, the specific targets of Cs1 within fish remained largely unknown.
“Three years prior, we struggled to pinpoint the target for the Conkunitzin toxin using the best available tools, which ultimately proved insufficient,” Karbat commented. “However, advances in structural biology powered by artificial intelligence have marked a significant turning point.”
In their recent study, Karbat and Reuveny employed dual computational strategies to isolate the fish potassium channels that are most susceptible to Cs1. Their approach started with the usage of AlphaFold, a sophisticated AI program that predicts the binding affinities of toxins to diverse potassium channels found in fish. Subsequently, they introduced ET3, a novel AI model designed to analyze the dynamic movement of water molecules around these channels.
The ET3 model was fine-tuned to detect anomalies in the flow of water around the channel’s selectivity filter, which regulates the permeability of ions. When Cs1 obstructs this filter, it effectively disables the channel. By assessing a broad spectrum of fish potassium channels, the researchers identified specific channels targeted by Cs1 and determined how the toxin interferes with their operation. Essentially, if potassium channels resemble tiny gates managing ionic flow into and out of cells, Cs1 functions as a lock that renders these gates inoperable.
“Utilizing molecular dynamics alongside newly developed AI-driven structural tools allowed us to pinpoint a small number of fish channels that bind our toxins with high affinity, likely representing the primary targets of the cone snail,” explained Karbat.
Kartbat further elaborated that this innovative pipeline presents vast potential for ecological research by enabling the study of genuine chemical interactions within ecosystems. Additionally, it holds promise for drug development, enabling researchers to identify targets based on a drug’s structure and discern potential off-target effects.
As an illustrative point, Karbat noted, “If a drug is engineered to activate a channel in the human brain, it should ideally not influence a channel in the heart, which could lead to life-threatening consequences.”
“The strength of our pipeline lies in its focus—it allows researchers to concentrate on specific targets or molecules of interest and discover their counterparts,” Reuveny added.
Citation: Cone snail toxin inspires new method for studying molecular interactions (2025, February 17) retrieved 17 February 2025 from here.
Source
phys.org