The rapid technological progress in the last centuries has been largely fueled by the success of the scientific method. However, in some of the most important fields, such as material or drug discovery, the productivity has been decreasing dramatically (Smietana et al., 2016) and by today it can take almost a decade to discover a new material and cost upwards of $10-$100 million. One of the most daunting challenges in materials discovery is hypothesis generation. The reservoir of natural products and their derivatives has been largely emptied (Atanasov et al., 2021) and bottom-up human-driven hypotheses have shown that it is extremely challenging to identify and select novel and useful candidates in search spaces that are overwhelming in size, e.g., the chemical space for drug-like molecules is estimated to contain > 10

With the fast development of COVID-19 into a global pandemic, scientists around the globe are desperately searching for effective antiviral therapeutic agents. Bridging systems biology and drug discovery, we propose a deep learning framework for conditional de novo design of antiviral candidate drugs tailored against given protein targets. First, we train a multimodal ligand--protein binding affinity model on predicting affinities of antiviral compounds to target proteins and couple this model with pharmacological toxicity predictors. Exploiting this multi-objective as a reward function of a conditional molecular generator (consisting of two VAEs), we showcase a framework that navigates the chemical space toward regions with more antiviral molecules. Specifically, we explore a challenging setting of generating ligands against unseen protein targets by performing a leave-one-out-cross-validation on 41 SARS-CoV-2-related target proteins. Using deep RL, it is demonstrated that in 35 out of 41 cases, the generation is biased towards sampling more binding ligands, with an average increase of 83% comparing to an unbiased VAE. We present a case-study on a potential Envelope-protein inhibitor and perform a synthetic accessibility assessment of the best generated molecules is performed that resembles a viable roadmap towards a rapid in-vitro evaluation of potential SARS-CoV-2 inhibitors.

Reliable identification of molecular biomarkers is essential for accurate patient stratification. While state-of-the-art machine learning approaches for sample classification continue to push boundaries in terms of performance, most of these methods are not able to integrate different data types and lack generalization power limiting their application in a clinical setting. Furthermore, many methods behave as black boxes, therefore we have very little understanding about the mechanisms that lead to the prediction provided. While opaqueness concerning machine behaviour might not be a problem in deterministic domains, in health care, providing explanations about the molecular factors and phenotypes that are driving the classification is crucial to build trust in the performance of the predictive system. We propose Pathway Induced Multiple Kernel Learning (PIMKL), a novel methodology to classify samples reliably that can, at the same time, provide a pathway-based molecular fingerprint of the signature that underlies the classification. PIMKL exploits prior knowledge in the form of molecular interaction networks and annotated gene sets, by optimizing a mixture of pathway-induced kernels using a Multiple Kernel Learning algorithm (MKL), an approach that has demonstrated excellent performance in different machine learning applications. After optimizing the combination of kernels for prediction of a specific phenotype, the model provides a stable molecular signature that can be interpreted in the light of the ingested prior knowledge and that can be used in transfer learning tasks.