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Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) offers a promising strategy to eliminate previously undruggable proteins. PROTACs are bifunctional molecules that link a target protein with an E3 ubiquitin ligase, enabling the formation of a ternary complex that promotes ubiquitination and subsequent proteasomal degradation. Although many ternary complex structures are available, understanding how structural features relate to PROTAC function remains challenging due to the dynamic nature of these complexes. Here we show that the interface between the target protein SMARCA2 and the E3 ligase VHL is conformationally flexible and stabilized by interactions involving disordered loops. Using molecular dynamics simulations and X-ray crystallography of SMARCA2–VHL complexes bound to five different PROTACs, we find that interfacial residues often adopt energetically suboptimal, or ‘frustrated,’ configurations. We further show that the degree of frustration correlates with experimentally measured cooperativity for a set of 11 PROTACs. These findings suggest that quantifying interface frustration provides a rational, structure-based approach to guiding PROTAC design. PROTACs induce degradation by bridging a target protein and E3 ubiquitin ligase. Here, authors show that protein interface frustration correlates with cooperativity, offering a structural metric to prioritize PROTAC candidates prior to synthesis.

Building on the role of human intuition in small molecule drug design, we explored whether crowdsourcing could recruit citizen scientists to this task while in parallel building awareness for this scientific process. Here, we introduce Drugit ( https://drugit.org ), the small molecule design mode of the online citizen science game Foldit. We demonstrate its utility by identifying distinct binders to the von Hippel Lindau E3 ligase. Several thousand molecules were suggested by players in a series of ten puzzle rounds. The proposed molecules were further evaluated in silico and manually by an expert panel. Selected candidates were synthesized and tested. One of these molecules shows dose-dependent shift perturbations in protein-observed NMR experiments. The co-crystal structure in complex with the E3 ligase reveals that the observed binding mode matches the player’s original idea. The completion of one full design cycle is a proof of concept for the Drugit approach and highlights the potential of involving citizen scientists in early drug discovery. Citizen science taps the efforts of non-experts. Here, authors describe Drugit, an extension of the crowdsourcing game Foldit, and its use in designing a non-peptide binder of Von Hippel Lindau E3 ligase for use with proteolysis targeting chimeras.

The Nakuru-Elmenteita basin in the Central Kenya Rift, contains two shallow, alkaline lakes, Lake Nakuru (1770 m above sea level) and Lake Elmenteita (1786 m). Ancient shorelines and lake sediments at 1940 m suggest that these two lakes formed a single large and deep lake as a result of a wetter climate during the early Holocene. Here, we used a hydrological model to compare the precipitation-evaporation balance during the early Holocene to today. Assuming that the Nakuru-Elmenteita basin was hydrologically closed, as it is today, the most likely climate scenario includes a 45% increase in mean-annual precipitation, a 0.5°C decrease in air temperature, and an increase of 9% in cloud coverage from the modern values. Compared to the modeling results from other East African lake basins, this dramatic increase in precipitation seems to be unrealistic. Therefore, we propose a significant flow of water from the early Holocene Lake Naivasha in the south towards the Nakuru-Elmenteita basin to compensate the extremely negative hydrological budget of this basin. Since we did not find any field evidence for a surface connection, as often proposed during the last 70 years, the hydrological deficit of the Nakuru-Elmenteita basin could have also been compensated by a subsurface water exchange.[PUBLICATION ABSTRACT]

Matrix metalloproteinases (MMPs) are zinc endopeptidases that are required for the degradation of extracellular matrix components during normal embryo development, morphogenesis and tissue remodelling. Their proteolytic activities are precisely regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance results in diseases such as arthritis, atherosclerosis, tumour growth and metastasis. Here we report the crystal structure of an MMP-TIMP complex formed between the catalytic domain of human stromelysin-1 (MMP-3) and human TIMP-1. TIMP-1, a 184-residue protein, has the shape of an elongated, contiguous wedge. With its long edge, consisting of five different chain regions, it occupies the entire length of the active-site cleft of MMP-3. The central disulphide-linked segments Cys 1-Thr 2-Cys 3-Val 4 and Ser 68-Val 69 bind to either side of the catalytic zinc. Cys 1 bidentally coordinates this zinc, and the Thr-2 side chain extends into the large specificity pocket of MMP-3. This unusual architecture of the interface between MMP-3 and TIMP-1 suggests new possibilities for designing TIMP variants and synthetic MMP inhibitors with potential therapeutic applications.

Computer-Aided Drug Design (CADD) is an integral part of the drug discovery endeavor at Boehringer Ingelheim (BI). CADD contributes to the evaluation of new therapeutic concepts, identifies small molecule starting points for drug discovery, and develops strategies for optimizing hit and lead compounds. The CADD scientists at BI benefit from the global use and development of both software platforms and computational services. A number of computational techniques developed in-house have significantly changed the way early drug discovery is carried out at BI. In particular, virtual screening in vast chemical spaces, which can be accessed by combinatorial chemistry, has added a new option for the identification of hits in many projects. Recently, a new framework has been implemented allowing fast, interactive predictions of relevant on and off target endpoints and other optimization parameters. In addition to the introduction of this new framework at BI, CADD has been focusing on the enablement of medicinal chemists to independently perform an increasing amount of molecular modeling and design work. This is made possible through the deployment of MOE as a global modeling platform, allowing computational and medicinal chemists to freely share ideas and modeling results. Furthermore, a central communication layer called the computational chemistry framework provides broad access to predictive models and other computational services.

Activating mutations in the three human RAS genes, , and , are among the most common oncogenic drivers in human cancers. Covalent KRAS inhibitors, which bind to the switch II pocket in the ‘off state’ of KRAS, represent the first direct KRAS drugs that entered human clinical trials. However, the remaining 85% of non-KRAS -driven cancers remain undrugged as do NRAS and HRAS and no drugs targeting the ‘on state’ have been discovered so far. The switch I/II pocket is a second pocket for which the nanomolar inhibitor BI-2852 has been discovered. Here, we elucidate inhibitor binding modes in KRAS, NRAS and HRAS on and off and discuss future strategies to drug all RAS isoforms with this one pocket.

Tryptases, the predominant serine proteinases of human mast cells, have recently been implicated as mediators in the pathogenesis of allergic and inflammatory conditions, most notably asthma. Their distinguishing features, their activity as a heparin-stabilized tetramer and resistance to most proteinaceous inhibitors, are perfectly explained by the 3- angstrom crystal structure of human β II-tryptase in complex with 4-amidinophenylpyruvic acid. The tetramer consists of four quasiequivalent monomers arranged in a flat frame-like structure. The active centers are directed toward a central pore whose narrow openings of approximately 40 angstrom × 15 angstrom govern the interaction with macromolecular substrates and inhibitors. The tryptase monomer exhibits the overall fold of trypsin-like serine proteinases but differs considerably in the conformation of six surface loops arranged around the active site. These loops border and shape the active site cleft to a large extent and form all contacts with neighboring monomers via two distinct interfaces. The smaller of these interfaces, which is exclusively hydrophobic, can be stabilized by the binding of heparin chains to elongated patches of positively charged residues on adjacent monomers or, alternatively, by high salt concentrations in vitro. On tetramer dissociation, the monomers are likely to undergo transformation into a zymogen-like conformation that is favored and stabilized by intramonomer interactions. The structure thus provides an improved understanding of the unique properties of the biologically active tryptase tetramer in solution and will be an incentive for the rational design of mono- and multifunctional tryptase inhibitors.

Oncogenic alterations in human epidermal growth factor receptor 2 (HER2) occur in approximately 2% of patients with non-small cell lung cancer and predominantly affect the tyrosine kinase domain and cluster in exon 20 of the ERBB2 gene. Most clinical-grade tyrosine kinase inhibitors are limited by either insufficient selectivity against wild-type (WT) epidermal growth factor receptor (EGFR), which is a major cause of dose-limiting toxicity or by potency against HER2 exon 20 mutant variants. Here we report the discovery of covalent tyrosine kinase inhibitors that potently inhibit HER2 exon 20 mutants while sparing WT EGFR, which reduce tumor cell survival and proliferation in vitro and result in regressions in preclinical xenograft models of HER2 exon 20 mutant non-small cell lung cancer, concomitant with inhibition of downstream HER2 signaling. Our results suggest that HER2 exon 20 insertion-driven tumors can be effectively treated by a potent and highly selective HER2 inhibitor while sparing WT EGFR, paving the way for clinical translation.Neumüller and colleagues identify and characterize potent HER2 exon 20 insertion-selective inhibitors with efficacy, which preserve wild-type epidermal growth factor receptor signaling in preclinical models of non-small cell lung cancer in vivo.