Virtual screening (VS) stands as a cornerstone of early-stage drug discovery, yet long-standing hurdles-including prohibitive computational cost and limited cross-target generalization-have long restricted its genome-wide application, especially with the rapid expansion of AlphaFold-predicted protein structures. Over the past 2 years, contrastive learning has emerged as a genuinely transformative paradigm, with DrugCLIP as a landmark implementation that reimagines virtual screening as fast embedding-based dense retrieval. This commentary offers a balanced overview of DrugCLIP's core innovations: its contrastive framework that aligns protein pocket and small-molecule representations, paired with GenPack for targeted pocket refinement of predicted structures. We synthesize recent benchmark results validating its performance relative to molecular docking and machine-learning baselines, recap wet-lab success stories across psychiatric and cancer-associated targets, and assess the real-world impact of the resulting GenomeScreenDB resource. We further place DrugCLIP in context with contemporary computational tools including RosettaVS, Deep Docking, and AF2-RAVE, highlight unresolved challenges such as translating binding predictions into functional activity and screening against tough PPI targets, and outline actionable avenues for future development. Taken together, this work illustrates how contrastive learning is quietly reshaping informatics-driven drug discovery and opening the undrugged genome to systematic exploration.

1,2-Fluorine migration in fluorocarbenes has long posed a formidable challenge, hindered by prohibitively high kinetic barriers. Herein, we report a formal 1,2-fluorine migration of trifluoromethyl and pentafluoroethyl diazo compounds catalyzed by a porphyrin-supported iridium complex under mild conditions, enabling straightforward access to structurally diverse fluorinated alkenes. Mechanistic investigations and density functional theory (DFT) calculations elucidate a catalytic cycle involving iridium-carbene formation and intermolecular fluoride transfer, wherein fluoride serves as a chain carrier to promote the formal 1,2-fluorine migration. This catalytic platform overcomes the intrinsic limitations of fluorine migration in fluorocarbenes and provides a complementary synthetic route to valuable fluorinated alkene scaffolds.

Small-molecule stabilization of G-quadruplexes (G4s) has become an active focus in nucleic acid-targeted drug discovery. The mechanisms of the ligands' binding selectivity and biological activities are critical for rational drug design. CX-5461, the first clinically advanced G4-targeting agent, has shown notable efficacy in DNA repair-deficient cancers. Its close analogue MTR-106 also displayed comparable anti-proliferative effects on cancer cells. However, the molecular basis of their interaction with G4s remains elusive. Here, through differential scanning calorimetry, complementary biophysical assays, and solution NMR technique, we probed their recognition modes with G4s. Although both ligands induced stronger thermal stabilization of the parallel G4s, the MYT1L quadruplex-duplex hybrid (QDH) formed the most homogeneous ligand-bound complexes in solution, highlighting the G4-duplex junction as a potential recognition site. Solution structural determination at high resolution demonstrated that both CX-5461 and MTR-106 inserted into the G4-duplex junction pocket. Their rigid polyaromatic scaffolds stacked with the 3 '-end G-tetrad of G4, while their flexible side chains extended into the groove of QDH to enable spatial recognition. These findings elucidated the molecular basis of G4 recognition by CX-5461 and MTR-106, and provided a structural framework for the rational development of next-generation G4-targeted therapeutics with improved selectivity and efficacy.

Transition metal-catalysed enantioselective radical transformations have emerged as powerful tools for the synthesis of chiral molecules, and a range of methods have been developed. However, most of these successful reactions are effective for resonance-stabilized radicals; in sharp contrast, achieving precise stereocontrol over highly reactive, unstabilized alkyl radicals remains a major challenge, with very few successful examples. Here we establish a ligand-mediated radical orientation strategy that enables the highly enantioselective cyanation of such transient intermediates via copper catalysis. The chiral BoxOH ligand engages in dynamic hydrogen bonding with various remote functional groups on the radical species, strategically reshaping the reaction energy landscape and overcoming the inherently barrierless radical coupling process to dictate stereoselectivity. Consequently, this method enables the direct asymmetric cyano-functionalization of unactivated alkenes and inert sp 3 C-H bonds, expanding asymmetric radical reactions beyond stabilized intermediates and providing a platform for the enantioselective functionalization of abundant chemical feedstocks.

AA-type alpha,omega-dihydroxy telechelic polyolefins (tPOs) are key macromonomers for the step-growth construction of circular polyolefin(-like) materials and, in particular, block-level sequence-controlled olefin block copolymers (OBCs), yet a general route to alpha,omega-dihydroxy tPOs directly from commodity ethylene/alpha-olefins has remained inaccessible. Here, a catalyst-free tandem Zn-B exchange/oxidation enables near-quantitative conversion of CCTP-derived poly(ethylene-co-alpha-olefin) polymeryl-Zn intermediates into AA-type alpha,omega-dihydroxy tPOs with >95% difunctional ratios while preserving industrially relevant microstructures and allowing scale-up to similar to 60 g per batch. These tPOs and their corresponding diester tPOs undergo polycondensation to afford alternating OBCs with controlled block lengths and tunable compositions. An architecture-controlled comparison with corresponding random analogs further shows that, although the overall composition primarily determines the total crystallinity, the alternating sequence leads to a more homogeneous nanoscale physical network, lower viscoelastic dissipation, more effective strain hardening, and improved cyclic stability with reduced stress relaxation. These results demonstrate that the AA-type telechelic platform not only expands telechelic polyolefin chemistry but also enables sequence-programmable polyolefin architectures with distinct and practically meaningful performance advantages, establishing sequence control as a powerful design lever for recyclable multiblock polyolefin materials.

Conventional sulfur vulcanization provides practical cross-linking for unsaturated rubbers but struggles to simultaneously improve tear resistance, impact durability, processing stability, and aging performance through a simple and scalable strategy. Herein, we report a calix[6]arene-mediated inverse vulcanization approach to engineer mechanically interlocked polysulfide cross-linkers for natural rubber/carbon black (NR/CB) composites. Two macrocyclic systems were designed to clarify the role of the interface integration. Tert-butylcalix[6]arene (TBC6), lacking polymerizable groups, forms polyrotaxane structures that operate primarily at the rubber-filler interface, enhancing bound rubber formation and enabling interfacial sliding. In contrast, allyl-functionalized calix[6]arene (ATBC6) covalently incorporates into the vulcanized network, constructing slidable cross-links within the bulk while simultaneously strengthening rubber-filler interfacial coupling. This coordinated network interface architecture promotes efficient stress transfer and suppresses crack propagation. The ATBC6-based composite exhibits a 140% increase in tear strength and a 340% enhancement in fracture toughness relative to those of conventional vulcanizates, accompanied by pronounced strain-rate hardening and improved energy absorption. Additionally, stable polysulfide linkages and phenolic units impart enhanced thermo-oxidative aging resistance. This scalable interface engineering strategy offers a practical pathway toward high-performance elastomer composites.

Biofilms formed by Shewanella oneidensis MR-1 are crucial for metal reduction, underpinning bioremediation and bioenergy applications, yet detailed structural insights into biofilm components remain limited. Here we show that MR-1 biofilms contain abundant filamentous networks, membrane vesicles, and distinct square-shaped aggregates, as revealed by cryo-electron tomography and cryo-electron microscopy. We further determine near-atomic resolution structures of three filament types: bacterial flagella and two distinct pili, PilA and MshA. We present high-resolution structures of an MshA pilus and a PilA pilus from Shewanella. Structural analyses show that MshA pili exhibit a balanced surface charge distribution and extensive solvent-accessible surface area, facilitating essential interactions within the biofilm matrix. Additionally, oxygen limitation markedly increases the abundance of extracellular filaments and protein aggregates, indicating adaptive responses to environmental stress. Our findings elucidate the fundamental architecture and roles of biofilm extracellular components and provide a structural foundation for engineering enhanced Shewanella strains.

The TMPRSS2:ERG gene fusion, present in approximately 50% of prostate cancers in patients of European ancestry, drives oncogenesis through aberrant overexpression of the ERG transcription factor. Despite its role as a truncal oncogenic driver, ERG has been considered undruggable due to the absence of enzymatic activity and apparent lack of ligandable pockets. Here, we demonstrate continued dependency on ERG in metastatic prostate cancer and identify a druggable pocket within its N-terminal Pointed (PNT) domain. Using an inducible shRNA system in TMPRSS2:ERG-positive VCaP cells, we show that ERG depletion causes profound growth inhibition. To therapeutically exploit this vulnerability, we conducted a domain-focused differential scanning fluorimetry screen targeting the ERG PNT domain, followed by structure-activity relationship optimization. This approach yielded PBITE-1 (PNT-Binding Inhibitor of the Transcription factor ERG), a small molecule that selectively binds the ERG PNT domain. NMR chemical-shift perturbation mapping and molecular docking revealed that PBITE-1 engages a discrete, solvent-exposed surface comprising two alpha-helices and an adjacent flexible loop, defining a ligand-binding pocket within the PNT domain. In cellular models, PBITE-1 directly engaged ERG, selectively inhibited proliferation and invasion, and induced apoptosis in ERG-driven prostate and hematologic malignancies. PBITE-1 potently suppressed growth of ERG-positive mouse and human-derived prostate cancer organoids. Furthermore, PBITE-1 treatment significantly induced tumor cell apoptosis in VCaP xenograft models. These findings establish the ERG PNT domain as ligandable and provide preclinical evidence that ERG is directly targetable by small molecules, enabling future development of ERG-directed inhibitors and targeted protein degraders.