AlphaFold accelerates artificial intelligence powered drug discovery: efficient discovery of a novel CDK20 small molecule inhibitor

Feng Ren, Xiao Ding, Min Zheng, Mikhail Korzinkin, Xin Cai, Wei Zhu, Alexey Mantsyzov, Alex Aliper, Vladimir Aladinskiy, Zhongying Cao, Shanshan Kong, Xi Long, Bonnie Hei Man Liu, Yingtao Liu, Vladimir Naumov, Anastasia Shneyderman, Ivan V. Ozerov, Ju Wang, Frank W. Pun, Alan Aspuru-Guzik, Michael Levitt, Alex Zhavoronkov

Introduction to AlphaFold and AI-powered drug discovery

In this scientific article, researchers demonstrate the use of the AlphaFold computer program to accelerate artificial intelligence (AI)-powered drug discovery. AlphaFold, developed by DeepMind, has the ability to predict protein structures. The researchers applied AlphaFold to their AI-powered drug discovery platforms, PandaOmics and Chemistry42, to identify a small molecule inhibitor for cyclin-dependent kinase 20 (CDK20), a protein associated with hepatocellular carcinoma (HCC), a type of liver cancer.

Analysis and synthesis of compounds using PandaOmics and Chemistry42

Using PandaOmics, the researchers analyzed text and OMICs data from multiple datasets to identify potential targets for HCC. CDK20 was selected as the target due to its strong association with HCC and limited structural information. Chemistry42 was then used to generate molecules based on the predicted CDK20 structure from AlphaFold. From the pool of generated molecules, seven compounds were synthesized and tested. One compound,

ISM042-2-001, demonstrated binding affinity to CDK20 with a Kd value of 9.2 ± 0.5 mM.

Successful application of AlphaFold predictions in drug discovery and future prospects

This work demonstrates the successful application of AlphaFold predictions in the drug discovery process, particularly for identifying hit molecules against novel targets with limited structural information. The integration of AI-powered platforms PandaOmics and Chemistry42 enabled the rapid discovery of a CDK20 inhibitor within 30 days. Further optimization and evaluation of the hit molecule are ongoing. This study highlights the potential of AI and protein structure prediction for accelerating drug discovery.

Link to Article: [2201.09647] AlphaFold Accelerates Artificial Intelligence Powered Drug Discovery: Efficient Discovery of a Novel Cyclin-dependent Kinase 20 (CDK20) Small Molecule Inhibitor (arxiv.org)

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