Oncotarget | https://doi.org/10.18632/oncotarget.14073 Artur Kadurin, Alexander Aliper, Andrey Kazennov, Polina Mamoshina, Quentin Vanhaelen, Kuzma Khrabrov, Alex Zhavoronkov The cornucopia of meaningful leads: Applying deep adversarial autoencoders for new molecule development in oncology

The applications of modern artificial intelligence (AI) algorithms within the field of aging research offer tremendous opportunities. Aging is an almost universal unifying feature possessed by all living organisms, tissues, and cells. Modern deep learning techniques used to develop age predictors offer new possibilities for formerly incompatible dynamic and static data types. AI biomarkers of aging enable a holistic view of biological processes and allow for novel methods for building causal models-extracting the most important features and identifying biological targets and mechanisms. Recent developments in generative adversarial networks (GANs) and reinforcement learning (RL) permit the generation of diverse synthetic molecular and patient data, identification of novel biological targets, and generation of novel molecular compounds with desired properties and geroprotectors. These novel techniques can be combined into a unified, seamless end-to-end biomarker development, target identification, drug discovery and real world evidence pipeline that may help accelerate and improve pharmaceutical research and development practices. Modern AI is therefore expected to contribute to the credibility and prominence of longevity biotechnology in the healthcare and pharmaceutical industry, and to the convergence of countless areas of research.

In this paper, we propose the deep neural network Adversarial Threshold Neural Computer (ATNC). The ATNC model is intended for the de novo design of novel small-molecule organic structures. The model is based on generative adversarial net- work architecture and reinforcement learning. ATNC uses a Differentiable Neural Com- puter as a generator and has a new specific block, called adversarial threshold (AT). AT acts as a filter between the agent (generator) and the environment (discriminator + objective reward functions). Furthermore, to generate more diverse molecules we introduce a new objective reward function named Internal Diversity Clustering (IDC). In this work, ATNC is tested and compared with the ORGANIC model. Both models were trained on the SMILES string representation of the molecules, using four objective functions (internal similarity, Muegge drug likeness filter, presence or absence of sp3-rich fragments and IDC). The SMILES representations of 15K drug-like molecules from the ChemDiv collection were used as a training dataset. For the different functions, ATNC outperforms ORGANIC. Combined with the IDC, ATNC generates 72% of valid and 77% of unique SMILES strings while ORGANIC generates only 7% of valid and 86% of unique SMILES strings. For each set of molecules generated by ATNC and ORGANIC, we analyzed distributions of four molecular descriptors (number of atoms, molecular weight, logP and tpsa) and calculated five chemical statistical features (internal di- versity, number of unique heterocycles, number of clusters, number of singletons and number of compounds that have not been passed through medicinal chemistry filters). Analysis of key molecular descriptors and chemical statistical features demonstrated that the molecules generated by ATNC elicited better druglikeness properties. We also performed in vitro validation of the molecules generated by ATNC; results indicated that ATNC is an effective method for producing hit compounds.