The fraction of sp3-hybridized carbons (Fsp3) and the fraction of stereogenic carbons (FCstereo) are two widely employed scores of molecular complexity with strong links to biologically relevant features. However, they do not comprehensively express molecular topology, and they often do not match the chemical intuition of complexity. We propose the spacial score (SPS) as an empirical scoring system that builds upon the principle underlying Fsp3 and FCstereo and expresses the spacial complexity of a compound in a uniform manner on a highly granular scale. The size-normalized SPS (nSPS) can differentiate distributions of natural products and synthetic compounds and is applicable in the analysis of biological activity data. Analysis of the ChEMBL database revealed general trends of increasing selectivity and potency with increasing nSPS. SPS can also be used advantageously in planning and analysis of synthesis programs for direct comparison of chemical transformations and intermediates in reaction sequences.

Mass-spectrometry-based phosphoproteomics enables the analysis of thousands of protein phosphorylation events across the human proteome. However, there is a lack of scalable, hypothesis-free, and stat...

A visible-light-controlled lysine-selective crosslinking (VL-XL) strategy is introduced for exploring protein complexes and dynamic interactomes in live cells. By synergistically integrating the adva...

Extracellular and membrane-associated proteins play essential roles in nearly all our body’s biochemical processes and are implicated in cancer, autoimmune disorders, and neurodegenerative diseases. Consequently, a selective and universally applicable technique for the degradation of these proteins in disease-relevant conditions could significantly improve human health prospects. Lysosome-targeting chimeras (LYTACs) are bifunctional degraders comprising of an antibody conjugated with a cell–surface receptor ligand that enables cargo lysosome shuttling and degradation. Herein, we demonstrate that conjugation of antibodies with a small ketoboronate-based, lysine-reactive, covalent-reversible uptake tag (KB) enables the internalization of plasma membrane and extracellular proteins, directing them to lysosomal degradation via receptor-mediated endocytosis. Chemoproteomic target deconvolution revealed that reversible modification of lysine residues on the transferrin receptor protein 1 (TFRC) and HLA class I histocompatibility antigen A, B and C (HLA-ABC) enabled efficient uptake and lysosomal targeting through both clathrin-dependent and -independent mechanisms. KB-antibody conjugates (KB-TACs) efficiently degrade the epidermal growth factor receptor (EGFR), vascular endothelial growth factor A (VEGFA) and epidermal growth factor receptor 2 (HER2) in cancer cells. Furthermore, we showed KB-TTZ degrades HER2 in vivo in BT-474 tumor xenografts, with a significant reduction in tumor volumes compared to TTZ and vehicle treatments. Altogether, the KB tag represents a versatile, minimal-size chemical unit to functionalize therapeutic antibodies for targeted protein degradation through dual receptor-mediated endocytosis and lysosomal delivery.

Activity-based protein profiling has identified hundreds of proteins from diverse classes that react at specific cysteine residues with stereochemically defined electrophilic compounds (stereoprobes) ...

As a member of the immune checkpoint, PD-1 is acknowledged as a key player in immune regulation and a hot target for cancer immunotherapy. The broad and flat binding interface of PD-1 to PD-L1 poses a...

The peptide-centric local stability assay (PELSA) can be used to determine ligand-binding targets and binding regions on a proteome-wide scale with high sensitivity.

Affinity-selection platforms are powerful tools in early drug discovery, but current technologies such as DNA-encoded libraries (DELs) are limited by synthesis complexity and incompatibility with nucl...

Proteins lacking defined ligandable pockets remain challenging drug targets. Here, we develop a molecular glue-based PROTAC (MGPROTACs) approach that chemically conjugates a molecular glue stabilizer ...

Discovering high-affinity ligands directly from protein structures remains a key challenge in drug discovery. BindCraft is a structure-guided generative modeling platform able to de novo design miniproteins with a high affinity for a large set of targets. While miniproteins are valuable research tools, short peptides offer substantially greater therapeutic potential. However, given their lack of stabilized tertiary structures, de novo generation of functional peptides is a remarkable challenge. Here, we show that BindCraft is able to generate high affinity peptides, solely based on target structure, with remarkable success rates. For the oncoprotein MDM2, BindCraft generated 70 unique peptides; 15 were synthesized, and 7 showed specific binding with nanomolar affinities. Competition assays confirmed site-specific binding for the intended target site. For another oncology target, WDR5, six out of nine candidates bound the MYC binding WBM site with submicromolar affinity. Bindcraft’s high fidelity structure prediction enabled one shot peptide optimization via rational chemical modification, improving the potency of one WDR5 binder by 6-fold to a KD of 39 nM. BindCraft also generated candidate peptides for targeting PD-1 and PD-L1. However, none of the tested peptides showed detectable binding. Together, these results establish a first evaluation of BindCraft for peptide binder prediction. Despite remaining limitations, this tool shows the potential to rival display technologies in delivering high-affinity ligands for therapeutic development.

Discovering high-affinity ligands directly from protein structures remains a key challenge in drug discovery. BindCraft is a structure-guided generative modeling platform able to de novo design miniproteins with a high affinity for a large set of targets. While miniproteins are valuable research tools, short peptides offer substantially greater therapeutic potential. However, given their lack of stabilized tertiary structures, de novo generation of functional peptides is a remarkable challenge. Here, we show that BindCraft is able to generate high affinity peptides, solely based on target structure, with remarkable success rates. For the oncoprotein MDM2, BindCraft generated 70 unique peptides; 15 were synthesized, and 7 showed specific binding with nanomolar affinities. Competition assays confirmed site-specific binding for the intended target site. For another oncology target, WDR5, six out of nine candidates bound the MYC binding WBM site with submicromolar affinity. Bindcraft’s high fidelity structure prediction enabled one shot peptide optimization via rational chemical modification, improving the potency of one WDR5 binder by 6-fold to a KD of 39 nM. BindCraft also generated candidate peptides for targeting PD-1 and PD-L1. However, none of the tested peptides showed detectable binding. Together, these results establish a first evaluation of BindCraft for peptide binder prediction. Despite remaining limitations, this tool shows the potential to rival display technologies in delivering high-affinity ligands for therapeutic development.

Chemical proteomics has brought rigor to covalent drug discovery and drugs to the clinic. Can it deliver a new generation of drug targets?