Advances in the discovery of new chemotypes through ultra-large library docking

Abstract

Introduction: The size and complexity of virtual screening libraries in drug discovery have skyrocketed in recent years, reaching up to multiple billions of accessible compounds. However, virtual screening of such ultra-large libraries poses several challenges associated with preparing the libraries, sampling, and pre-selection of suitable compounds. The utilization of artificial intelligence (AI)-assisted screening approaches, such as deep learning, poses a promising countermeasure to deal with this rapidly expanding chemical space. For example, various AI-driven methods were recently successfully used to identify novel small molecule inhibitors of the SARS-CoV-2 main protease (M^pro).

Areas covered: This review focuses on presenting various kinds of virtual screening methods suitable for dealing with ultra-large libraries. Challenges associated with these computational methodologies are discussed, and recent advances are highlighted in the example of the discovery of novel M^pro inhibitors targeting the SARS-CoV-2 virus.

Expert opinion: With the rapid expansion of the virtual chemical space, the methodologies for docking and screening such quantities of molecules need to keep pace. Employment of AI-driven screening compounds has already been shown to be effective in a range from a few thousand to multiple billion compounds, furthered by de novo generation of drug-like molecules without human interference.

Keywords: Drug discovery; SARS-CoV-2; deep-learning; large-scale ligand libraries; protein-ligand docking; virtual screening.