73 research outputs found

    Cross-species chemogenomic profiling reveals evolutionarily conserved drug mode of action

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    Chemogenomic screens were performed in both budding and fission yeasts, allowing for a cross-species comparison of drug–gene interaction networks.Drug–module interactions were more conserved than individual drug–gene interactions.Combination of data from both species can improve drug–module predictions and helps identify a compound's mode of action

    Amide-to-ester substitution as a strategy for optimizing PROTAC permeability and cellular activity

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    Bifunctional PROTAC degraders belong to "beyond Rule of 5" chemical space, and criteria for predicting their drug-like properties are underdeveloped. PROTAC components are often combined via late-stage amide couplings, due to the reliability and robustness of amide bond formation. Amides, however, can give rise to low cellular permeability and poor ADME properties. We hypothesized that a bioisosteric replacement of an amide with a less polar ester could lead to improvements in both physicochemical properties and bioactivity. Using a library of model compounds, bearing either amides or esters at various linker-warhead junctions, we identify parameters for optimal compound lipophilicity and permeability. We next applied these learnings to design a set of novel amide-to-ester substituted, VHL-based BET degraders with increased permeability. Our ester-PROTACs remarkably retained intracellular stability, were overall more potent degraders than their amide counterparts and showed an earlier onset of the hook effect. These enhanced cellular features were found to be driven by greater cell permeability rather than improvements in ternary complex formation. This largely unexplored amide-to-ester substitution therefore provides a simple and practical strategy to enhance PROTAC permeability and degradation performance. Such approach could prove equally beneficial to other classes of beyond Ro5 molecules.

    A new amino acid for improving permeability and solubility in macrocyclic peptides through side chain-to-backbone hydrogen bonding.

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    Despite the notoriously poor membrane permeability of peptides in general, many cyclic peptide natural products show high passive membrane permeability and potently inhibit a variety of “undruggable” intracellular targets. A major impediment to designing cyclic peptides with good permeability is the high desolvation energy associated with the peptide backbone amide NH groups. Strategies for mitigating the deleterious effect of the backbone NH group on permeability include N-methylation, steric occlusion, and the formation of intramolecular hydrogen bonds with backbone carbonyl oxygens, while there have been relatively few studies on the use of polar side chains to sequester backbone NH groups. We investigated the ability of N,N-pyrrolidinyl glutamine (Pye), whose side chain contains a powerful hydrogen bond accepting C=O amide group but no hydrogen bond donors, to sequester exposed backbone NH groups in a series of cyclic hexapeptide diastereomers. Analyses of partition coefficients, lipophilic permeability efficiencies (LPE), artificial and cell-based permeability assays revealed that specific Leu-to-Pye substitutions conferred dramatic improvements in aqueous solubility and permeability in a scaffold- and position-dependent manner. Introduction of the Pye residue thus offers a complementary tool, alongside traditional approaches, for improving membrane permeability and solubility in cyclic peptides

    Amide-to-ester substitution as a strategy for optimizing PROTAC permeability and cellular activity

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    [Image: see text] Criteria for predicting the druglike properties of “beyond Rule of 5” Proteolysis Targeting Chimeras (PROTAC) degraders are underdeveloped. PROTAC components are often combined via amide couplings due to their reliability. Amides, however, can give rise to poor absorption, distribution, metabolism, and excretion (ADME) properties. We hypothesized that a bioisosteric amide-to-ester substitution could lead to improvements in both physicochemical properties and bioactivity. Using model compounds, bearing either amides or esters, we identify parameters for optimal lipophilicity and permeability. We applied these learnings to design a set of novel amide-to-ester-substituted, VHL-based BET degraders with the goal to increase permeability. Our ester PROTACs retained intracellular stability, were overall more potent degraders than their amide counterparts, and showed an earlier onset of the hook effect. These enhancements were driven by greater cell permeability rather than improvements in ternary complex formation. This largely unexplored amide-to-ester substitution provides a simple strategy to enhance PROTAC permeability and bioactivity and may prove beneficial to other beyond Ro5 molecules

    Retrospective analysis of natural products provides insights for future discovery trends

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    Understanding of the capacity of the natural world to produce secondary metabolites is important to a broad range of fields, including drug discovery, ecology, biosynthesis, and chemical biology, among others. Both the absolute number and the rate of discovery of natural products have increased significantly in recent years. However, there is a perception and concern that the fundamental novelty of these discoveries is decreasing relative to previously known natural products. This study presents a quantitative examination of the field from the perspective of both number of compounds and compound novelty using a dataset of all published microbial and marine-derived natural products. This analysis aimed to explore a number of key questions, such as how the rate of discovery of new natural products has changed over the past decades, how the average natural product structural novelty has changed as a function of time, whether exploring novel taxonomic space affords an advantage in terms of novel compound discovery, and whether it is possible to estimate how close we are to having described all of the chemical space covered by natural products. Our analyses demonstrate that most natural products being published today bear structural similarity to previously published compounds, and that the range of scaffolds readily accessible from nature is limited. However, the analysis also shows that the field continues to discover appreciable numbers of natural products with no structural precedent. Together, these results suggest that the development of innovative discovery methods will continue to yield compounds with unique structural and biological properties
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