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The Reg: Why does AlphaFold struggle to simulate docking accurately? Was it trained for this task? We had some questions for Felix Wong and Aarti Krishnan, the lead authors for the MIT study. Neither of those are helped much at all by knowing protein structures,' Lowe added. And those are picking the right targets and getting early warnings about toxicity. 'The biggest problems in drug discovery are the ones that contribute to our roughly 85 percent failure rate in the clinic. But to me, this isn't so much on AlphaFold as it is on docking technology.'ĪlphaFold may prove useful for other parts of the drug discovery pipeline, where comparing protein structures obtained via different methods against the model's predictions is valuable. 'Even with perfect protein structures, some of them are going to be better 'fits' for a docking-and-scoring approach than others, and AlphaFold structures, while impressive, are not perfect, either.

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Added to that is the way that different docking software will give you different answers, and for any given target one of them might give notably more useful answers than another - but again, you don't know up front which of those it'll be,' Lowe said. 'Virtual screening has never yet reached the 'works every time' level - sometimes it provides useful information and sometimes it doesn't, and you are never sure up front which of those regimes you're working in. Even if scientists have a good model of the protein, its shape changes when it is interacting with a potential drug candidate in mysterious ways. 'Docking small molecules into a given protein structure is really a different problem than determining that protein structure in the first place,' he said.īeing able to model these types of chemical interactions is an unsolved problem. LinkedIn billionaire Reid Hoffman, DeepMind co-founder launch AI startupĭerek Lowe, a longtime drug discovery chemist and science writer, told The Register he wasn't surprised with the results given that AlphaFold was not really trained for molecular docking simulations.

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'We found that if you were to filter the interactions using those additional models, you can get a higher ratio of true positives to false positives.' 'The machine-learning models learn not just the shapes, but also chemical and physical properties of the known interactions, and then use that information to reassess the docking predictions,' he said. Other machine learning models were more accurate than AlphaFold for some simulations, according to Felix Wong, co-author of the paper and a postdoctoral researcher at MIT. 'Utilizing these standard molecular docking simulations, we obtained an auROC value of roughly 0.5, which basically says you're doing no better than if you were randomly guessing,' Collins said. AlphaFold was not very effective for modelling molecular docking simulations accurately. coli bacteria with 218 antibacterial compounds, including antibiotics such as tetracyclines. The team tested AlphaFold's ability to model interactions between 296 essential proteins from E. A molecule that binds strongly to a protein is more likely to be an effective drug it could be more effective at preventing the protein from carrying out a pathogenic function, such as tumor growth, for example. The goal was to use molecular docking to rank the candidate compounds by how strongly they bind to the target protein. 'Our study speaks to both the current abilities and the current limitations of computational platforms for drug discovery.'Ĭollins and his colleagues used AlphaFold to simulate interactions between bacterial proteins and antibacterial compounds, a task known as molecular docking. 'Breakthroughs such as AlphaFold are expanding the possibilities for in silico (computer simulation) drug discovery efforts, but these developments need to be coupled with additional advances in other aspects of modeling that are part of drug discovery efforts,' James Collins, lead author of the study published in Molecular Systems Biology and a bioengineering professor at MIT, said in a statement.

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