期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：51
DOI：10.1073/pnas.2112621118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Structure-based drug design depends on the ability to predict both the three-dimensional structures of candidate molecules bound to their targets and the associated binding affinities. We demonstrate that one can substantially improve the accuracy of these predictions using easily obtained data about completely different molecules that bind to the same target without requiring any target-bound structures of these molecules. The approach we developed to integrate physical and data-driven modeling may find a variety of applications in the rapidly growing field of artificial intelligence for drug discovery.
Over the past five decades, tremendous effort has been devoted to computational methods for predicting properties of ligands—i.e., molecules that bind macromolecular targets. Such methods, which are critical to rational drug design, fall into two categories: physics-based methods, which directly model ligand interactions with the target given the target’s three-dimensional (3D) structure, and ligand-based methods, which predict ligand properties given experimental measurements for similar ligands. Here, we present a rigorous statistical framework to combine these two sources of information. We develop a method to predict a ligand’s pose—the 3D structure of the ligand bound to its target—that leverages a widely available source of information: a list of other ligands that are known to bind the same target but for which no 3D structure is available. This combination of physics-based and ligand-based modeling improves pose prediction accuracy across all major families of drug targets. Using the same framework, we develop a method for virtual screening of drug candidates, which outperforms standard physics-based and ligand-based virtual screening methods. Our results suggest broad opportunities to improve prediction of various ligand properties by combining diverse sources of information through customized machine-learning approaches.
关键词：structural biology; drug design; artificial intelligence; antipsychotics; virtual screening
