Advancing Ligand Docking through Deep Learning: Challenges and Prospects in Virtual Screening

Molecular docking, also termed ligand docking (LD), is a pivotal element of structure-based virtual screening (SBVS) used to predict the binding conformations and affinities of protein–ligand complexes. Traditional LD methodologies rely on a search and scoring framework, utilizing heuristic algorithms to explore binding conformations and scoring functions to evaluate binding strengths. However, to meet the efficiency demands of SBVS, these algorithms and functions are often simplified, prioritizing speed over accuracy.

The emergence of deep learning (DL) has exerted a profound impact on diverse fields, ranging from natural language processing to computer vision and drug discovery. DeepMind’s AlphaFold2 has impressively exhibited its ability to accurately predict protein structures solely from amino acid sequences, highlighting the remarkable potential of DL in conformation prediction. This groundbreaking advancement circumvents the traditional search-scoring frameworks in LD, enhancing both accuracy and processing speed and thereby catalyzing a broader adoption of DL algorithms in binding pose prediction. Nevertheless, a consensus on certain aspects remains elusive.

In this Account, we delineate the current status of employing DL to augment LD within the VS paradigm, highlighting our contributions to this domain. Furthermore, we discuss the challenges and future prospects, drawing insights from our scholarly investigations. Initially, we present an overview of VS and LD, followed by an introduction to DL paradigms, which deviate significantly from traditional search-scoring frameworks. Subsequently, we delve into the challenges associated with the development of DL-based LD (DLLD), encompassing evaluation metrics, application scenarios, and physical plausibility of the predicted conformations. In the evaluation of LD algorithms, it is essential to recognize the multifaceted nature of the metrics. While the accuracy of binding pose prediction, often measured by the success rate, is a pivotal aspect, the scoring/screening power and computational speed of these algorithms are equally important given the pivotal role of LD tools in VS. Regarding application scenarios, early methods focused on blind docking, where the binding site is unknown. However, recent studies suggest a shift toward identifying binding sites rather than solely predicting binding poses within these models. In contrast, LD with a known pocket in VS has been shown to be more practical. Physical plausibility poses another significant challenge. Although DLLD models often achieve higher success rates compared to traditional methods, they may generate poses with implausible local structures, such as incorrect bond angles or lengths, which are disadvantageous for postprocessing tasks like visualization. Finally, we discuss the future perspectives for DLLD, emphasizing the need to improve generalization ability, strike a balance between speed and accuracy, account for protein conformation flexibility, and enhance physical plausibility. Additionally, we delve into the comparison between generative and regression algorithms in this context, exploring their respective strengths and potential.