A Hitchhiker's Guide to Deep Chemical Language Processing for Bioactivity Prediction

Deep learning has significantly accelerated drug discovery, with 'chemical language' processing (CLP) emerging as a prominent approach. CLP learns from molecular string representations (e.g., Simplified Molecular Input Line Entry Systems [SMILES] and Self-Referencing Embedded Strings [SELFIES]) with methods akin to natural language processing. Despite their growing importance, training predictive CLP models is far from trivial, as it involves many 'bells and whistles'. Here, we analyze the key elements of CLP training, to provide guidelines for newcomers and experts alike. Our study spans three neural network architectures, two string representations, three embedding strategies, across ten bioactivity datasets, for both classification and regression purposes. This 'hitchhiker's guide' not only underscores the importance of certain methodological choices, but it also equips researchers with practical recommendations on ideal choices, e.g., in terms of neural network architectures, molecular representations, and hyperparameter optimization.

Structure-based drug discovery with deep learning

Artificial intelligence (AI) in the form of deep learning bears promise for drug discovery and chemical biology, $\textit{e.g.}$, to predict protein structure and molecular bioactivity, plan organic synthesis, and design molecules $\textit{de novo}$. While most of the deep learning efforts in drug discovery have focused on ligand-based approaches, structure-based drug discovery has the potential to tackle unsolved challenges, such as affinity prediction for unexplored protein targets, binding-mechanism elucidation, and the rationalization of related chemical kinetic properties. Advances in deep learning methodologies and the availability of accurate predictions for protein tertiary structure advocate for a $\textit{renaissance}$ in structure-based approaches for drug discovery guided by AI. This review summarizes the most prominent algorithmic concepts in structure-based deep learning for drug discovery, and forecasts opportunities, applications, and challenges ahead.

Geometric Deep Learning on Molecular Representations

Geometric deep learning (GDL), which is based on neural network architectures that incorporate and process symmetry information, has emerged as a recent paradigm in artificial intelligence. GDL bears particular promise in molecular modeling applications, in which various molecular representations with different symmetry properties and levels of abstraction exist. This review provides a structured and harmonized overview of molecular GDL, highlighting its applications in drug discovery, chemical synthesis prediction, and quantum chemistry. Emphasis is placed on the relevance of the learned molecular features and their complementarity to well-established molecular descriptors. This review provides an overview of current challenges and opportunities, and presents a forecast of the future of GDL for molecular sciences.

Drug discovery with explainable artificial intelligence

Deep learning bears promise for drug discovery, including advanced image analysis, prediction of molecular structure and function, and automated generation of innovative chemical entities with bespoke properties. Despite the growing number of successful prospective applications, the underlying mathematical models often remain elusive to interpretation by the human mind. There is a demand for 'explainable' deep learning methods to address the need for a new narrative of the machine language of the molecular sciences. This review summarizes the most prominent algorithmic concepts of explainable artificial intelligence, and dares a forecast of the future opportunities, potential applications, and remaining challenges.