The discovery of small molecules with therapeutic potential is a long-standing challenge in chemistry and biology. Researchers have increasingly leveraged novel computational techniques to streamline the drug development process to increase hit rates and reduce the costs associated with bringing a drug to market. To this end, we introduce a quantum-classical generative model that seamlessly integrates the computational power of quantum algorithms trained on a 16-qubit IBM quantum computer with the established reliability of classical methods for designing small molecules. Our hybrid generative model was applied to designing new KRAS inhibitors, a crucial target in cancer therapy. We synthesized 15 promising molecules during our investigation and subjected them to experimental testing to assess their ability to engage with the target. Notably, among these candidates, two molecules, ISM061-018-2 and ISM061-22, each featuring unique scaffolds, stood out by demonstrating effective engagement with KRAS. ISM061-018-2 was identified as a broad-spectrum KRAS inhibitor, exhibiting a binding affinity to KRAS-G12D at $1.4 \mu M$. Concurrently, ISM061-22 exhibited specific mutant selectivity, displaying heightened activity against KRAS G12R and Q61H mutants. To our knowledge, this work shows for the first time the use of a quantum-generative model to yield experimentally confirmed biological hits, showcasing the practical potential of quantum-assisted drug discovery to produce viable therapeutics. Moreover, our findings reveal that the efficacy of distribution learning correlates with the number of qubits utilized, underlining the scalability potential of quantum computing resources. Overall, we anticipate our results to be a stepping stone towards developing more advanced quantum generative models in drug discovery.

Structure-based drug discovery (SBDD) is a standard method for identifying prospective medications for a target by leveraging its structural information. AlphaFold, a technique for predicting protein structure, has been regarded as a helpful resource for the discovery of therapeutics for new targets with low or no structural knowledge. In this study, the scientists utilized AlphaFold predictions as input for their AI-powered drug discovery engines (PandaOmics and Chemistry42) to efficiently identify a potential drug for CDK20 within 30 days. Understanding the structure of proteins is important in order to figure out their functions and the effect of change in amino acid sequence. The 3D structure of a protein allows us to visualize its functions and how genes and diseases are connected.

Deep learning in biopharma has come of age. After working for years to understand how to apply an artificial intelligence (AI) approach to biotechnology, Insilico Medicine recently disclosed the discovery of a novel drug target and novel molecule using AI. The discovery, a world first, took less than 18 months and cost 10% as much as a conventional program. Having validated its platforms, Insilico is now making the technology available to big pharmaceutical companies. Insilico was founded in 2014 by a team of long-term academic collaborators, Alex Zhavoronkov and Alex Aliper.

The AlphaFold computer program predicted protein structures for the whole human genome, which has been considered as a remarkable breakthrough both in artificial intelligence (AI) application and structural biology. Despite the varying confidence level, these predicted structures still could significantly contribute to structure-based drug design of novel targets, especially the ones with no or limited structural information. In this work, we successfully applied AlphaFold in our end-to-end AI-powered drug discovery engines constituted of a biocomputational platform PandaOmics and a generative chemistry platform Chemistry42, to identify a first-in-class hit molecule of a novel target without an experimental structure starting from target selection towards hit identification in a cost- and time-efficient manner. PandaOmics provided the targets of interest and Chemistry42 generated the molecules based on the AlphaFold predicted structure, and the selected molecules were synthesized and tested in biological assays. Through this approach, we identified a small molecule hit compound for CDK20 with a Kd value of 8.9 +/- 1.6 uM (n = 4) within 30 days from target selection and after only synthesizing 7 compounds. Based on the available data, the second round of AI-powered compound generation was conducted and through which, a more potent hit molecule, ISM042-2 048, was discovered with a Kd value of 210.0 +/- 42.4 nM (n = 2), within 30 days and after synthesizing 6 compounds from the discovery of the first hit ISM042-2-001. To the best of our knowledge, this is the first reported small molecule targeting CDK20 and more importantly, this work is the first demonstration of AlphaFold application in the hit identification process in early drug discovery.

Abstract: Chemistry42 is a software platform for de novo small molecule design that integrates Artificial Intelligence (AI) techniques with computational and medicinal chemistry methods. Chemistry42 is unique in its ability to generate novel molecular structures with predefined properties validated through in vitro and in vivo studies. Keywords: generative chemistry, target identification, deep learning, reinforcement learning, drug discovery, de novo drug design Introduction Deep Learning (DL) has proven to be very effective in speech and image recognition. This is because DL-based architectures are uniquely suited for the automatic identification of patterns within complex, nonlinear data sets without the need for manual feature engineering. DL methods have successfully overcome limitations inherent in the standard techniques used for small molecule design (Chen et al. 2018; Vanhaelen, Lin, and Zhavoronkov 2020; Yang et al. 2019) which offers exciting possibilities for the development of new methods that efficiently explore uncharted chemical space.