LinkerBridge is proposed, an equivariant framework that unifies biochemical semantics with physical constraints through two innovations: a Contextual Interaction-Aware Representation module that internalizes pre-existing bio-chemical semantics and a Differentiable Physical Guidance mechanism derived from Van der Waals potentials to steer generation away from collision zones.
Linkers play a central role in many areas of medicinal chemistry, including proximity inducers, small‐molecule conjugates, and DNA‐encoded libraries. However, little is known about the accessibility of molecules to linker attachment when bound to proteins. Here, we analyze linker accessibility across protein–ligand complexes in cocrystal structures. A computational workflow was developed to evaluate the linkerability of modifiable positions on molecules based on solvent accessibility, local steric space for introduction of a linker atom, and the geometry of solvent‐directed escape paths approximated as conical frustums. Analysis of 8,228 protein–ligand cocrystal structures with 131 431 modifiable positions shows that approximately 22% of positions can accommodate linkers without significant geometric restriction. Limited linkerability of positions influences DEL data and may confound efforts to use such data for lead prediction.
The central theme, conformational analysis, links on-target potency via pre-organization of the bioactive conformation with physics-based physicochemical property prediction with physics-based physicochemical property prediction, highlighting neutral polarity as a key determinant of permeability and exposure.
Metal-organic frameworks (MOFs) with precisely modified pore environments are essential for applications in catalysis, gas capture, and gas sensing. However, creating these highly selective sites through straightforward synthetic routes remains a challenge. Herein, we present a design strategy for UiO-type MOFs that enables control over the precise placement of functional groups within the tetrahedral pores of the framework, distinguishing it from less precise post-synthetic modification methods. By crosslinking two linker molecules with a short functional urea bridge pre-synthetically, the combination of the resulting linker geometry and the UiO-66 framework confines the crosslink to the trigonal pore windows. This results in pocket-like arrangements, as the urea bridges effectively "wall off" some of the pore windows. The structural implications are supported by modelling and electron crystallography. To demonstrate the functional versatility, we probe the selectivity of the obtained MOF toward aliphatic nitro compounds at low concentrations using vapor sorption measurements and compare it with other UiO-66 derivatives.
Tobias Hennig, Erik Rohloff, Verena Drewes et al.· Angewandte Chemie· 0 citations
Boltz2ESI is introduced, an end-to-end framework that predicts enzyme–substrate interactions by leveraging structural knowledge learned by a biomolecular foundation model and consistently outperforms state-of-the-art sequence-based and rigid-docking approaches.
Xiwei Cheng, Seonghwan Seo, C. Huh et al.· bioRxiv· 0 citations
EvoBind-multimer is presented, a deep learning framework for the de novo design of molecular glues directly from protein sequences that generates small macrocyclic peptides that bridge user-defined protein pairs without requiring prior interface knowledge or existing ligands.
Andrä Brunner, Krzysztof Wierbiłowicz, Diandra Daumiller et al.· bioRxiv· 0 citations
Scaffold-Guided Structure Refinement is presented, leveraging information on known binders within ligand series targeting a specific protein, based on the observation that shared molecular scaffolds among binders exhibit conserved binding modes.
J. Pletzer-Zelgert, Matthias Rarey, Bernd Kuhn· Journal of Medicinal Chemist...· 0 citations
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