The use of AI in drug development | Explained

What are target proteins and how are they identified? How do AI-based tools AlphaFold 3 and RoseTTAFold All-Atom help in predicting the correct target protein and its interactions with drugs? Where does India stand in the field of computational drug development?

Published - May 16, 2024 10:40 pm IST

For representative purposes.

For representative purposes. | Photo Credit: Getty Images

Drug development is an expensive and time-consuming process. However, the advent of Artificial Intelligence (AI) has opened up a world of possibilities with respect to fast-tracking drug development.

How does the process start?

The process of developing a drug starts with identifying and validating a target. A target is a biological molecule (usually a gene or a protein) to which a drug directly binds in order to work. The overwhelming majority of targets are proteins. Only those proteins with ideal sites where drugs can go and dock to do their business are druggable proteins.

Target proteins are identified in the discovery phase, wherein a target protein sequence is fed into a computer which looks for the best-fitting drug out of millions in the library of small molecules for which the structures are stored in the computer. The process assumes that the structures of the target protein and drug are known. If not, the computer uses models to understand the sites where a drug can bind. This discovery process avoids time-consuming laboratory experiments that require expensive chemicals and reagents and have a high failure rate. Once the suitable protein target and its drug are identified, the research moves to the pre-clinical phase, where the potential drug candidates are tested outside a biological system, using cells and animals for the drug’s safety and toxicity. After this, as part of the clinical phase, the drug is tested on a small number of human patients before being used on more patients for efficacy and safety. Finally, the drug undergoes regulatory approval and marketing and post-market survey phases. Due to a high failure rate, the discovery phase limits the number of drugs that pass and carry on to the pre-clinical and clinical phases.

How can AI help this process?

AI has the potential to revolutionise target discovery and understand drug-target interaction by drastically cutting down time, increasing the accuracy of prediction of interaction between a drug and its target, and saving money. The development of two AI-based prediction tools, AlphaFold and RoseTTAFold, developed by researchers at DeepMind, a Google company, and the University of Washington, U.S., respectively, has provided a major scientific breakthrough in the last four years in the area of computational drug development. Both tools are based on deep neural networks. The tools’ neural networks use massive amounts of input data to produce the desired output — the three-dimensional structures of proteins. Published recently, the new avatars of AlphaFold and RoseTTAFold, called AlphaFold 3 (developed jointly by Isomorphic Labs, a DeepMind spinoff) and RoseTTAFold All-Atom, respectively, take the capability of these tools to an entirely new level. The significant difference between the upgraded versions and their previous forms is their capability to predict not just static structures of proteins and protein-protein interactions but also their ability to predict structures and interactions for any combination of protein, DNA, and RNA, including modifications, small molecules and ions. Additionally, the new versions use generative diffusion-based architectures (one kind of AI model) to predict structural complexes. In a test with 400 interactions between targets and their small molecule drugs, AlphaFold 3 accurately predicted their interactions 76% of the time versus 40% by RoseTTAFold All-Atom.

What are the drawbacks?

With all the promise and potential in drug development, AI tools have limitations. For example, the tools can, at best, provide up to 80% accuracy in predicting interactions (the accuracy comes down drastically for protein-RNA interaction predictions). Second, the tools can only aid a single phase of drug development, target discovery and drug-target interaction. It will still have to go through the pre-clinical and clinical development phases, and there is no guarantee that the AI-derived molecules will result in success in those phases. Third, one of the challenges with diffusion-based architecture is model hallucinations, where insufficient training data causes the tool to produce incorrect or non-existent predictions. Finally, unlike the previous versions of AlphaFold, DeepMind has not released the code for AlphaFold 3, restricting its independent verification, broad utilisation and use for protein-small molecule interaction studies.

What about India?

Developing new AI tools for drug development requires large-scale computing infrastructure, especially ones with fast Graphics Processing Units (GPUs) to run multiple tasks with longer sequences. GPU chips are expensive, and with newer and faster ones being produced by hardware makers every year, they have a quick expiration date. India needs such large-scale computing infrastructure. That, along with a lack of skilled AI scientists, unlike in the U.S. and China, is the second reason why researchers in India could not establish a first-mover advantage in developing AI tools for drug development despite the country having a rich history in protein X-ray crystallography, modelling and other fields of structural biology. However, with a growing number of pharmaceutical organisations, India can lead the way in applying AI tools in target discovery, identification, and drug testing.

Binay Panda is Professor at JNU, New Delhi and posts at @ganitlabs.

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