Daniil Polykovskiy, Alexander Zhebrak, Benjamin Sanchez-Lengeling et al.
Generative models are becoming a tool of choice for exploring the molecular space. These models learn on a large training dataset and produce novel molecular structures with similar properties. Generated structures can be utilized for virtual screening or training semi-supervised predictive models in the downstream tasks. While there are plenty of generative models, it is unclear how to compare and rank them. In this work, we introduce a benchmarking platform called Molecular Sets (MOSES) to standardize training and comparison of molecular generative models. MOSES provides a training and testing datasets, and a set of metrics to evaluate the quality and diversity of generated structures. We have implemented and compared several molecular generation models and suggest to use our results as reference points for further advancements in generative chemistry research. The platform and source code are available at https://github.com/molecularsets/moses.
Mohammad Ghazi Vakili, Christoph Gorgulla, AkshatKumar Nigam et al.
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 $1.4 μM$. 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.
Alex Zhavoronkov, Dominika Wilczok, Roman Yampolskiy
Since the rapid expansion of large language models (LLMs), people have begun to rely on them for information retrieval. While traditional search engines display ranked lists of sources shaped by search engine optimization (SEO), advertising, and personalization, LLMs typically provide a synthesized response that feels singular and authoritative. While both approaches carry risks of bias and omission, LLMs may amplify the effect by collapsing multiple perspectives into one answer, reducing users ability or inclination to compare alternatives. This concentrates power over information in a few LLM vendors whose systems effectively shape what is remembered and what is overlooked. As a result, certain narratives, individuals or groups, may be disproportionately suppressed, while others are disproportionately elevated. Over time, this creates a new threat: the gradual erasure of those with limited digital presence, and the amplification of those already prominent, reshaping collective memory. To address these concerns, this paper presents a concept of the Right To Be Remembered (RTBR) which encompasses minimizing the risk of AI-driven information omission, embracing the right of fair treatment, while ensuring that the generated content would be maximally truthful.
Artem Zholus, Maksim Kuznetsov, Roman Schutski et al.
Generating novel active molecules for a given protein is an extremely challenging task for generative models that requires an understanding of the complex physical interactions between the molecule and its environment. In this paper, we present a novel generative model, BindGPT which uses a conceptually simple but powerful approach to create 3D molecules within the protein's binding site. Our model produces molecular graphs and conformations jointly, eliminating the need for an extra graph reconstruction step. We pretrain BindGPT on a large-scale dataset and fine-tune it with reinforcement learning using scores from external simulation software. We demonstrate how a single pretrained language model can serve at the same time as a 3D molecular generative model, conformer generator conditioned on the molecular graph, and a pocket-conditioned 3D molecule generator. Notably, the model does not make any representational equivariance assumptions about the domain of generation. We show how such simple conceptual approach combined with pretraining and scaling can perform on par or better than the current best specialized diffusion models, language models, and graph neural networks while being two orders of magnitude cheaper to sample.
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.
Yan A. Ivanenkov, Alex Zhebrak, Dmitry Bezrukov et al.
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. Chemistry42 is a core component of Insilico Medicine Pharma.ai drug discovery suite that also includes target discovery and multi-omics data analysis (PandaOmics) and clinical trial outcomes predictions (InClinico).
Konstantin Chekanov, Polina Mamoshina, Roman V. Yampolskiy et al.
Diversity is one of the fundamental properties for the survival of species, populations, and organizations. Recent advances in deep learning allow for the rapid and automatic assessment of organizational diversity and possible discrimination by race, sex, age and other parameters. Automating the process of assessing the organizational diversity using the deep neural networks and eliminating the human factor may provide a set of real-time unbiased reports to all stakeholders. In this pilot study we applied the deep-learned predictors of race and sex to the executive management and board member profiles of the 500 largest companies from the 2016 Forbes Global 2000 list and compared the predicted ratios to the ratios within each company's country of origin and ranked them by the sex-, age- and race- diversity index (DI). While the study has many limitations and no claims are being made concerning the individual companies, it demonstrates a method for the rapid and impartial assessment of organizational diversity using deep neural networks.
Yuri Nikolsky, Roman Gurinovich, Oleg Kuryan et al.
Despite the success of PubMed and other search engines in managing the massive volume of biomedical literature and the retrieval of individual publications, grant-related data remains scattered and relatively inaccessible. This is problematic, as project and funding data has significant analytical value and could be integral to publication retrieval. Here, we introduce GrantMed, a searchable international database of biomedical grants that integrates some 20 million publications with the nearly 1.4 million research projects and 650 billion dollars of funding that made them possible. For any given topic in the life sciences, Grantmed provides instantaneous visualization of the past 30 years of dollars spent and projects awarded, along with detailed individual project descriptions, funding amounts, and links to investigators, research organizations, and resulting publications. It summarizes trends in funding and publication rates for areas of interest and merges data from various national grant databases to create one international grant tracking system. This information will benefit the research community and funding entities alike. Users can view trends over time or current projects underway and use this information to navigate the decision-making process in moving forward. They can view projects prior to publication and records of previous projects. Convenient access to this data for analytical purposes will be beneficial in many ways, helping to prevent project overlap, reduce funding redundancy, identify areas of success, accelerate dissemination of ideas, and expose knowledge gaps in moving forward. It is our hope that this will be a central resource for international life sciences research communities and the funding organizations that support them, ultimately streamlining progress.