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  1. Article ; Online: Preparing for the next pandemic.

    Shoichet, Brian K / Craik, Charles S

    Science (New York, N.Y.)

    2023  Volume 382, Issue 6671, Page(s) 649–650

    Abstract: New lead drugs to treat COVID-19 are beginning to emerge. ...

    Abstract New lead drugs to treat COVID-19 are beginning to emerge.
    MeSH term(s) Humans ; COVID-19/prevention & control ; Pandemics/prevention & control ; COVID-19 Drug Treatment ; Drug Discovery ; Coronavirus Protease Inhibitors/chemistry ; Coronavirus Protease Inhibitors/pharmacology ; Coronavirus 3C Proteases/antagonists & inhibitors
    Chemical Substances Coronavirus Protease Inhibitors ; Coronavirus 3C Proteases (EC 3.4.22.28) ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-)
    Language English
    Publishing date 2023-11-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.adk5868
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Modeling the expansion of virtual screening libraries.

    Lyu, Jiankun / Irwin, John J / Shoichet, Brian K

    Nature chemical biology

    2023  Volume 19, Issue 6, Page(s) 712–718

    Abstract: Recently, 'tangible' virtual libraries have made billions of molecules readily available. Prioritizing these molecules for synthesis and testing demands computational approaches, such as docking. Their success may depend on library diversity, their ... ...

    Abstract Recently, 'tangible' virtual libraries have made billions of molecules readily available. Prioritizing these molecules for synthesis and testing demands computational approaches, such as docking. Their success may depend on library diversity, their similarity to bio-like molecules and how receptor fit and artifacts change with library size. We compared a library of 3 million 'in-stock' molecules with billion-plus tangible libraries. The bias toward bio-like molecules in the tangible library decreases 19,000-fold versus those 'in-stock'. Similarly, thousands of high-ranking molecules, including experimental actives, from five ultra-large-library docking campaigns are also dissimilar to bio-like molecules. Meanwhile, better-fitting molecules are found as the library grows, with the score improving log-linearly with library size. Finally, as library size increases, so too do rare molecules that rank artifactually well. Although the nature of these artifacts changes from target to target, the expectation of their occurrence does not, and simple strategies can minimize their impact.
    MeSH term(s) Libraries, Digital ; Molecular Docking Simulation
    Language English
    Publishing date 2023-01-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/s41589-022-01234-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Synthetic Ionizable Colloidal Drug Aggregates Enable Endosomal Disruption.

    Donders, Eric N / Slaughter, Kai V / Dank, Christian / Ganesh, Ahil N / Shoichet, Brian K / Lautens, Mark / Shoichet, Molly S

    Advanced science (Weinheim, Baden-Wurttemberg, Germany)

    2023  Volume 10, Issue 13, Page(s) e2300311

    Abstract: Colloidal drug aggregates enable the design of drug-rich nanoparticles; however, the efficacy of stabilized colloidal drug aggregates is limited by entrapment in the endo-lysosomal pathway. Although ionizable drugs are used to elicit lysosomal escape, ... ...

    Abstract Colloidal drug aggregates enable the design of drug-rich nanoparticles; however, the efficacy of stabilized colloidal drug aggregates is limited by entrapment in the endo-lysosomal pathway. Although ionizable drugs are used to elicit lysosomal escape, this approach is hindered by toxicity associated with phospholipidosis. It is hypothesized that tuning the pK
    MeSH term(s) Fulvestrant/metabolism ; Colloids ; Endosomes/metabolism ; Lysosomes
    Chemical Substances Fulvestrant (22X328QOC4) ; Colloids
    Language English
    Publishing date 2023-03-11
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2808093-2
    ISSN 2198-3844 ; 2198-3844
    ISSN (online) 2198-3844
    ISSN 2198-3844
    DOI 10.1002/advs.202300311
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  4. Article ; Online: Drug building blocks and libraries at risk in Ukraine.

    Kondratov, Ivan S / Moroz, Yurii S / Irwin, John J / Shoichet, Brian K

    Science (New York, N.Y.)

    2022  Volume 376, Issue 6596, Page(s) 929

    MeSH term(s) Armed Conflicts ; Pharmaceutical Preparations/chemical synthesis ; Risk ; Small Molecule Libraries ; Ukraine
    Chemical Substances Pharmaceutical Preparations ; Small Molecule Libraries
    Language English
    Publishing date 2022-05-26
    Publishing country United States
    Document type Letter
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.abq7841
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  5. Article: Colloidal aggregation confounds cell-based Covid-19 antiviral screens.

    Glenn, Isabella S / Hall, Lauren N / Khalid, Mir M / Ott, Melanie / Shoichet, Brian K

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Colloidal aggregation is one of the largest contributors to false-positives in early drug discovery and chemical biology. Much work has focused on its impact on pure-protein screens; here we consider aggregations role in cell-based infectivity assays in ... ...

    Abstract Colloidal aggregation is one of the largest contributors to false-positives in early drug discovery and chemical biology. Much work has focused on its impact on pure-protein screens; here we consider aggregations role in cell-based infectivity assays in Covid-19 drug repurposing. We began by investigating the potential aggregation of 41 drug candidates reported as SARs-CoV-2 entry inhibitors. Of these, 17 formed colloidal-particles by dynamic light scattering and exhibited detergent-dependent enzyme inhibition. To evaluate antiviral efficacy of the drugs in cells we used spike pseudotyped lentivirus and pre-saturation of the colloids with BSA. The antiviral potency of the aggregators was diminished by at least 10-fold and often entirely eliminated in the presence of BSA, suggesting antiviral activity can be attributed to the non-specific nature of the colloids. In confocal microscopy, the aggregates induced fluorescent puncta of labeled spike protein, consistent with sequestration of the protein on the colloidal particles. Addition of either non-ionic detergent or of BSA disrupted these puncta. These observations suggest that colloidal aggregation is common among cell-based anti-viral drug repurposing, and perhaps cell-based assays more broadly, and offers rapid counter-screens to detect and eliminate these artifacts, allowing the community invest resources in compounds with true potential as a Covid-19 therapeutic.
    Language English
    Publishing date 2023-10-30
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.27.564435
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Protein Stability Effects in Aggregate-Based Enzyme Inhibition.

    Torosyan, Hayarpi / Shoichet, Brian K

    Journal of medicinal chemistry

    2019  Volume 62, Issue 21, Page(s) 9593–9599

    Abstract: Small-molecule aggregates are a leading cause of artifacts in early drug discovery, but little is known about their interactions with proteins, nor why some proteins are more susceptible to inhibition than others. A possible reason for this apparent ... ...

    Abstract Small-molecule aggregates are a leading cause of artifacts in early drug discovery, but little is known about their interactions with proteins, nor why some proteins are more susceptible to inhibition than others. A possible reason for this apparent selectivity is that aggregation-based inhibition, as a stoichiometric process, is sensitive to protein concentration, which varies across assays. Alternatively, local protein unfolding by aggregates may lead to selectivity since stability varies among proteins. To deconvolute these effects, we used differentially stable point mutants of a single protein, TEM-1 β-lactamase. Broadly, destabilized mutants had higher affinities for and were more potently inhibited by aggregates versus more stable variants. The addition of the irreversible inhibitor moxalactam destabilized several mutants, and these typically bound tighter to a colloidal particle, while the only mutant it stabilized bound weaker. These results suggest that less-stable enzymes are more easily sequestered and inhibited by colloidal aggregates.
    MeSH term(s) Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Mutation ; Protein Stability ; Thermodynamics ; beta-Lactamases/genetics ; beta-Lactamases/metabolism
    Chemical Substances Enzyme Inhibitors ; beta-Lactamases (EC 3.5.2.6) ; beta-lactamase TEM-1 (EC 3.5.2.6)
    Language English
    Publishing date 2019-10-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.9b01019
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  7. Article ; Online: Drug discovery: follow your lead.

    Shoichet, Brian K

    Nature chemical biology

    2014  Volume 10, Issue 4, Page(s) 244–245

    MeSH term(s) Antineoplastic Combined Chemotherapy Protocols/chemical synthesis ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Drug Design ; Humans ; Polypharmacology ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/pharmacology
    Chemical Substances Protein Kinase Inhibitors
    Language English
    Publishing date 2014-03-18
    Publishing country United States
    Document type News ; Comment
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/nchembio.1484
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  8. Article: Structure-based discovery of CFTR potentiators and inhibitors.

    Liu, Fangyu / Kaplan, Anat Levit / Levring, Jesper / Einsiedel, Jürgen / Tiedt, Stephanie / Distler, Katharina / Omattage, Natalie S / Kondratov, Ivan S / Moroz, Yurii S / Pietz, Harlan L / Irwin, John J / Gmeiner, Peter / Shoichet, Brian K / Chen, Jue

    bioRxiv : the preprint server for biology

    2024  

    Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, while its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or ... ...

    Abstract The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, while its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify novel CFTR modulators. We docked ~155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered novel mid-nanomolar potentiators as well as inhibitors that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.
    Language English
    Publishing date 2024-03-11
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.09.09.557002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Colloidal aggregators in biochemical SARS-CoV-2 repurposing screens.

    Oâ Donnell, Henry R / Tummino, Tia A / Bardine, Conner / Craik, Charles S / Shoichet, Brian K

    bioRxiv : the preprint server for biology

    2021  

    Language English
    Publishing date 2021-08-31
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2021.08.31.458413
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Small vs. Large Library Docking for Positive Allosteric Modulators of the Calcium Sensing Receptor.

    Liu, Fangyu / Wu, Cheng-Guo / Tu, Chia-Ling / Glenn, Isabella / Meyerowitz, Justin / Levit Kaplan, Anat / Lyu, Jiankun / Cheng, Zhiqiang / Tarkhanova, Olga O / Moroz, Yurii S / Irwin, John J / Chang, Wenhan / Shoichet, Brian K / Skiniotis, Georgios

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Drugs acting as positive allosteric modulators (PAMs) to enhance the activation of the calcium sensing receptor (CaSR) and to suppress parathyroid hormone (PTH) secretion can treat hyperparathyroidism but suffer from side effects including hypocalcemia ... ...

    Abstract Drugs acting as positive allosteric modulators (PAMs) to enhance the activation of the calcium sensing receptor (CaSR) and to suppress parathyroid hormone (PTH) secretion can treat hyperparathyroidism but suffer from side effects including hypocalcemia and arrhythmias. Seeking new CaSR modulators, we docked libraries of 2.7 million and 1.2 billion molecules against transforming pockets in the active-state receptor dimer structure. Consistent with simulations suggesting that docking improves with library size, billion-molecule docking found new PAMs with a hit rate that was 2.7-fold higher than the million-molecule library and with hits up to 37-fold more potent. Structure-based optimization of ligands from both campaigns led to nanomolar leads, one of which was advanced to animal testing. This PAM displays 100-fold the potency of the standard of care, cinacalcet, in
    Language English
    Publishing date 2024-03-06
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.12.27.573448
    Database MEDical Literature Analysis and Retrieval System OnLINE

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