AI-driven computational drug design: tools, workflow and challenges

Abstract

Drug discovery is a time-consuming and resource-intensive process with a development period of more than ten years and a clinical attrition rate of more than 90%. Despite its contributions to rational drug design, computer-aided drug design has been constrained by limited scalability, overreliance on molecular descriptors, and incomplete modeling of complex biological systems. The emergence of artificial intelligence (AI) has transformed this landscape. AI-based drug discovery platforms have shifted the paradigm from a narrow focus to a comprehensive platform that covers target identification using graph-based drug-target interaction models. Additionally, deep-learning-based docking techniques, such as GNINA and AtomNet, de novo design approaches, such as REINVENT and RANC, and multi-task ADMET predictors, such as ADMETlab 2.0, are all parts of the AI-based drug discovery platform. In addition, AlphaFold has recently predicted more than 200 million protein structures, substantially expanding the pool of accessible drug targets. This review focuses on the AI-based approaches for target discovery, virtual screening, molecular generation, lead optimization, retro-synthesis, and structural modeling while also addressing issues of dataset bias, reproducibility, and real-world applicability. In this review, we discuss the emerging trends of AI-based drug discovery computational tools, which might change the face of medicinal chemistry. This review provides a balanced overview of AI-based drug discovery, including the limitations and challenges, to provide a framework to move this emerging field of science to a more robust, reproducible and clinically applicable platform.