Structure-based drug design depends on the ability to predict the three-dimensional structure of ligands bound to their targets, as does understanding the molecular mechanisms of many essential biological processes. Dozens of computational docking methods have been developed to address this binding pose prediction problem, but they frequently produce inaccurate results. Here we present a method that substantially improves the accuracy of binding pose prediction by exploiting a widely available source of non-structural information: a list of other ligands that bind the same target. Our method, ComBind, quantifies and leverages the chemist's intuition that even very different ligands tend to form similar interactions with a target protein. We demonstrate that ComBind consistently increases pose prediction accuracy across all major families of drug targets. We also illustrate its use by predicting previously unknown binding poses of antipsychotics and validating these results experimentally.

Cell cycle (CC) is a fundamental biological process with robust, cyclical gene expression programs to facilitate cell division. In the immune system, a productive immune response requires the expansion of pathogen-responsive cell types, but whether CC also confers unique gene expression programs that inform the subsequent immunological response remains unclear. Here we demonstrate that single macrophages adopt different plasticity states in CC, which is a major source of heterogeneity in response to polarizing cytokines. Specifically, macrophage plasticity to interferon gamma (IFNG) is substantially reduced, while interleukin 4 (IL-4) can induce S-G2/M-biased gene expression. Additionally, IL-4 polarization shifts the CC-phase distribution of the population towards G2/M phase, providing a mechanism for reduced IFNG-induced repolarization. Finally, we show that macrophages express tissue remodeling genes in the S-G2/M-phases of CC, that can be also detected in vivo during muscle regeneration. Therefore, macrophage inflammatory and regenerative responses are gated by CC in a cyclical phase-dependent manner.