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KAIST Surpasses the Limits of AlphaFold… AI Now Predicts Whether Drugs Actually Work
<(From Left) Ph.D candidate Hyojin Son, Professor Gwan-su Yi>
Proteins in our body function like switches. When a drug binds to a protein, the structure at the binding site changes, and this structural change propagates throughout the protein, turning its function on or off. Google DeepMind’s AlphaFold3 successfully predicted whether drugs bind to proteins and the three-dimensional structure of binding sites. However, it could not predict how signals propagate inside the protein after drug binding, how the entire structure changes, or whether the protein’s function is ultimately activated or inhibited. KAIST researchers have developed an AI that predicts not only whether a drug binds but whether it actually works.
KAIST (President Kwang Hyung Lee) announced on the 4th of March that a research team led by Professor Gwan-Su Yi of the Department of Bio and Brain Engineering has developed an artificial intelligence model called “GPCRact” that predicts whether candidate molecules not only bind to G-protein-coupled receptors (GPCRs)—a major drug target—but also actually activate the protein.
GPCRs act as “signal receivers” on the surface of cells. When hormones, neurotransmitters, or drugs send signals from outside the cell, GPCRs function as gates that receive these signals and transmit them into the cell. There are about 800 types of GPCRs in the human body, and roughly 30–40% of currently marketed drugs target them. They are key proteins involved in numerous physiological functions, including heart rate regulation, blood pressure control, pain sensing, immune responses, and emotional regulation.
However, a drug binding to a GPCR does not always trigger the desired biological function. Structural changes inside the protein and subsequent signal transmission determine whether the drug actually produces an effect. This process is known as allosteric signal propagation.
The research team designed the AI to learn the drug action process in two stages: ① the drug–target binding stage, and ② the intracellular signal propagation stage within the protein. The three-dimensional protein structure was represented as an atom-level graph, and an attention mechanism was applied to enable the model to learn important signaling pathways. Through this approach, the AI analyzes not only the drug binding signal but also the internal signaling pathways of the protein to predict whether the protein becomes activated.
As a result, the model significantly improved the prediction performance of drug activity even in proteins with complex structures that existing models struggled to analyze. Importantly, the model does not simply output “active” or “inactive.” It also presents the key internal signaling pathways that form the basis of its predictions, overcoming the limitations of so-called “black-box AI.”
<Schematic diagram of drug activity prediction and mechanism interpretation using the GPCRact artificial intelligence model>
This represents an important advance, as it allows researchers to interpret and verify predictions while simultaneously improving the reliability and efficiency of drug discovery. In the future, the model is expected to serve as a precision drug discovery AI platform capable of predicting not only whether drugs bind to GPCRs but also whether they truly activate them in various diseases targeting GPCRs.
<AI-generated image to help illustrate the research>
Professor Gwan-Su Yi explained, “Allosteric structural change refers to a phenomenon in which a drug binds to one part of a protein and its influence propagates internally, altering the function of other regions,” adding, “The key contribution of this research is incorporating this operational principle into deep learning.” He further noted, “We plan to expand the model to various proteins and ultimately develop technologies capable of predicting cellular and whole-body responses.”
Ph.D candidate Hyojin Son participated as the first author in this study. The paper was published on January 15 in the international journal Briefings in Bioinformatics, one of the leading journals in the field of bioinformatics.
※ Paper title: “GPCRact: a hierarchical framework for predicting ligand-induced GPCR activity via allosteric communication modeling”
DOI: https://doi.org/10.1093/bib/bbaf719※ Author information: Hyojin Son (KAIST, first author), Gwan-Su Yi (KAIST, corresponding author)
This research was supported by the Basic Research Program for Individual Research funded by the Ministry of Science and ICT and the National Research Foundation of Korea (RS-2025-24533057).
2026.03.09 View 2063 -
Ultrafast, on-Chip PCR Could Speed Up Diagnoses during Pandemics
A rapid point-of-care diagnostic plasmofluidic chip can deliver result in only 8 minutes
Reverse transcription-polymerase chain reaction (RT-PCR) has been the gold standard for diagnosis during the COVID-19 pandemic. However, the PCR portion of the test requires bulky, expensive machines and takes about an hour to complete, making it difficult to quickly diagnose someone at a testing site. Now, researchers at KAIST have developed a plasmofluidic chip that can perform PCR in only about 8 minutes, which could speed up diagnoses during current and future pandemics.
The rapid diagnosis of COVID-19 and other highly contagious viral diseases is important for timely medical care, quarantining and contact tracing. Currently, RT-PCR uses enzymes to reverse transcribe tiny amounts of viral RNA to DNA, and then amplifies the DNA so that it can be detected by a fluorescent probe. It is the most sensitive and reliable diagnostic method.
But because the PCR portion of the test requires 30-40 cycles of heating and cooling in special machines, it takes about an hour to perform, and samples must typically be sent away to a lab, meaning that a patient usually has to wait a day or two to receive their diagnosis.
Professor Ki-Hun Jeong at the Department of Bio and Brain Engineering and his colleagues wanted to develop a plasmofluidic PCR chip that could quickly heat and cool miniscule volumes of liquids, allowing accurate point-of-care diagnoses in a fraction of the time. The research was reported in ACS Nano on May 19.
The researchers devised a postage stamp-sized polydimethylsiloxane chip with a microchamber array for the PCR reactions. When a drop of a sample is added to the chip, a vacuum pulls the liquid into the microchambers, which are positioned above glass nanopillars with gold nanoislands. Any microbubbles, which could interfere with the PCR reaction, diffuse out through an air-permeable wall. When a white LED is turned on beneath the chip, the gold nanoislands on the nanopillars quickly convert light to heat, and then rapidly cool when the light is switched off.
The researchers tested the device on a piece of DNA containing a SARS-CoV-2 gene, accomplishing 40 heating and cooling cycles and fluorescence detection in only 5 minutes, with an additional 3 minutes for sample loading. The amplification efficiency was 91%, whereas a comparable conventional PCR process has an efficiency of 98%. With the reverse transcriptase step added prior to sample loading, the entire testing time with the new method could take 10-13 minutes, as opposed to about an hour for typical RT-PCR testing. The new device could provide many opportunities for rapid point-of-care diagnostics during a pandemic, the researchers say.
-Publication
Ultrafast and Real-Time Nanoplasmonic On-Chip Polymerase Chain Reaction for Rapid and Quantitative Molecular Diagnostics
ACS Nano (https://doi.org/10.1021/acsnano.1c02154)
-Professor
Ki-Hun Jeong
Biophotonics Laboratory
https://biophotonics.kaist.ac.kr/
Department of Bio and Brain Engineeinrg
KAIST
2021.06.08 View 19212 -
Universal Virus Detection Platform to Expedite Viral Diagnosis
Reactive polymer-based tester pre-screens dsRNAs of a wide range of viruses without their genome sequences
The prompt, precise, and massive detection of a virus is the key to combat infectious diseases such as Covid-19. A new viral diagnostic strategy using reactive polymer-grafted, double-stranded RNAs will serve as a pre-screening tester for a wide range of viruses with enhanced sensitivity.
Currently, the most widely using viral detection methodology is polymerase chain reaction (PCR) diagnosis, which amplifies and detects a piece of the viral genome. Prior knowledge of the relevant primer nucleic acids of the virus is quintessential for this test.
The detection platform developed by KAIST researchers identifies viral activities without amplifying specific nucleic acid targets. The research team, co-led by Professor Sheng Li and Professor Yoosik Kim from the Department of Chemical and Biomolecular Engineering, constructed a universal virus detection platform by utilizing the distinct features of the PPFPA-grafted surface and double-stranded RNAs.
The key principle of this platform is utilizing the distinct feature of reactive polymer-grafted surfaces, which serve as a versatile platform for the immobilization of functional molecules. These activated surfaces can be used in a wide range of applications including separation, delivery, and detection. As long double-stranded RNAs are common byproducts of viral transcription and replication, these PPFPA-grafted surfaces can detect the presence of different kinds of viruses without prior knowledge of their genomic sequences.
“We employed the PPFPA-grafted silicon surface to develop a universal virus detection platform by immobilizing antibodies that recognize double-stranded RNAs,” said Professor Kim.
To increase detection sensitivity, the research team devised two-step detection process analogues to sandwich enzyme-linked immunosorbent assay where the bound double-stranded RNAs are then visualized using fluorophore-tagged antibodies that also recognize the RNAs’ double-stranded secondary structure.
By utilizing the developed platform, long double-stranded RNAs can be detected and visualized from an RNA mixture as well as from total cell lysates, which contain a mixture of various abundant contaminants such as DNAs and proteins.
The research team successfully detected elevated levels of hepatitis C and A viruses with this tool.
“This new technology allows us to take on virus detection from a new perspective. By targeting a common biomarker, viral double-stranded RNAs, we can develop a pre-screening platform that can quickly differentiate infected populations from non-infected ones,” said Professor Li.
“This detection platform provides new perspectives for diagnosing infectious diseases. This will provide fast and accurate diagnoses for an infected population and prevent the influx of massive outbreaks,” said Professor Kim.
This work is featured in Biomacromolecules. This work was supported by the Agency for Defense Development (Grant UD170039ID), the Ministry of Science and ICT (NRF-2017R1D1A1B03034660, NRF-2019R1C1C1006672), and the KAIST Future Systems Healthcare Project from the Ministry of Science and ICT (KAISTHEALTHCARE42).
Profile:-Professor Yoosik KimDepartment of Chemical and Biomolecular Engineeringhttps://qcbio.kaist.ac.kr
KAIST-Professor Sheng LiDepartment of Chemical and Biomolecular Engineeringhttps://bcpolymer.kaist.ac.kr
KAIST
Publication:Ku et al., 2020. Reactive Polymer Targeting dsRNA as Universal Virus Detection Platform with Enhanced Sensitivity. Biomacromolecules (https://doi.org/10.1021/acs.biomac.0c00379).
2020.06.01 View 25428 -
Low Cost and Simple Gene Analysis Technology Developed
Professor Park Hyun Kyu of the Department of Biology and Chemical Engineering has developed a ‘real time CPR’ using Methylene Blue (nucleic acid bonding molecule with Electro-Chemical property).
The current gene analysis being used in the field is the real time PCR (Polymerase Chain Reaction) which takes advantage of the luminescent property of the gene and therefore requires expensive machines and chemicals to run.
By contrast, the electro-chemical method is easy to use and low cost and, most importantly, it allows the machine to become small and portable.
Professor Park’s research team used the decrease in the electro-chemical signal when the Methylene Blue reacts with nucleic acid and applied this to PCR which allowed for the real time analysis of the nucleic acid amplification process.
With the result of the experiment as the basis, the team was able to perform a trial with Chlamydia trachomatis, a pathogen that causes sexually transmitted disease.
The result showed that the electro-chemical method showed the same performance level as the real time PCR, which proved that the technology can be applied to diagnosing various diseases and gene research.
2011.04.30 View 14339