Drug development based on target proteins has been a successful approach in recent decades. However, the conventional structure-based drug design (SBDD) pipeline is a complex, human-engineered process with multiple independently optimized steps. Here, we propose a sequence-to-drug concept for computational drug design based on protein sequence information by end-to-end differentiable learning. We validate this concept in three stages. First, we design TransformerCPI2.0 as a core tool for the concept, which demonstrates generalization ability across proteins and compounds. Second, we interpret the binding knowledge that TransformerCPI2.0 learned. Finally, we use TransformerCPI2.0 to discover new hits for challenging drug targets, and identify new target for an existing drug based on an inverse application of the concept. Overall, this proof-of-concept study shows that the sequence-to-drug concept adds a perspective on drug design. It can serve as an alternative method to SBDD, particularly for proteins that do not yet have high-quality 3D structures available.
Deubiquitinase USP28 plays a crucial role in tumorigenesis by enhancing the stabilities of multiple cancer‐related proteins including c‐Myc, Notch1, and LSD1, and has become an attractive target for anticancer drug development. However, to date, only a few of USP28‐targeted active compounds have been developed, and the active compound‐binding pocket in USP28 has not been experimentally revealed yet. In this study, bioassay‐based high‐throughput screening was applied to discover USP28‐targeted inhibitors from the commercially available drug library. Vismodegib, an inhibitor of Hedgehog signaling pathway and FDA‐approved drug for the treatment of basal cell carcinoma, was found to exhibit inhibition activity against USP28 (IC50: 4.41 ± 1.08 μm). Multiple biophysical and biochemical techniques including NMR, ITC, thermal shift assay, HDX‐MS, and site‐directed mutagenesis analysis were then used to characterize the interaction between Vismodegib and USP28. The binding pocket in USP28 for Vismodegib, which is mainly composed of two helical structures spanning D255‐N278 and N286‐Y293, was revealed. According to the possible binding pose generated by HDX‐MS data‐defined molecular docking, the binding cavity occupied by Vismodegib in USP28 aligns well with one of the reported‐binding pockets in USP7 for its inhibitors. Furthermore, cellular assays were conducted to confirm that Vismodegib could interact with the evolutionarily related deubiquitinases USP28 and USP25 and downregulate the levels of the two enzymes' substrate proteins c‐Myc, Notch1, and Tankyrase‐1/2.
Disruption of EZH2−embryonic ectoderm development (EED) protein−protein interaction (PPI) is a new promising cancer therapeutic strategy. We have previously reported the discovery of astemizole, a small-molecule inhibitor targeting the EZH2−EED PPI. Herein, we report the cocrystal structure of EED in complex with astemizole at 2.15 Å. The structure elucidates the detailed binding mode of astemizole to EED and provides a structure-guided design for the discovery of a novel EZH2−EED interaction inhibitor, DC-PRC2in-01, with an affinity K d of 4.56 μM. DC-PRC2in-01 destabilizes the PRC2 complex, thereby leading to the degradation of PRC2 core proteins and the decrease of global H3K27me3 levels in cancer cells. The proliferation of PRC2-driven lymphomas cells is effectively inhibited, and the cell cycle is arrested in the G0/G1 phase. Together, these data demonstrate that DC-PRC2in-01 could be an effective chemical probe for investigating the PRC2-related physiology and pathology and providing a promising chemical scaffold for further development.
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