Target-Based Evaluation of “Drug-Like” Properties and Ligand Efficiencies

Leeson, Paul D.; Bento, A. Patrícia; Gaulton, Anna; Hersey, Anne; Manners, Emma; Radoux, Chris J.; Leach, Andrew R.

doi:10.1021/acs.jmedchem.1c00416

Cited by 69 publications

(82 citation statements)

References 112 publications

(260 reference statements)

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“…Triazole 8l has physicochemical and molecular properties consistent with drug-like space. 50 It was noteworthy that 8l had a much lower measured distribution coefficient (LogD 7.4 1.3 ± 0.05) than had been predicted by the calculated partition coefficient ( c log P 3.9) despite being non-ionized at physiologically relevant pH. This disconnection could be attributed to the close proximity of the 2-Cl, 3-CF 3 , and 4-Cl substituents on the aromatic ring that results in a reduction in overall hydrophobic surface area when compared to summing their individual lipophilicity fragmental constants (π).…”

Section: Resultsmentioning

confidence: 99%

Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit

et al. 2022

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Notum is a carboxylesterase that suppresses Wnt signaling through deacylation of an essential palmitoleate group on Wnt proteins. There is a growing understanding of the role Notum plays in human diseases such as colorectal cancer and Alzheimer’s disease, supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we have described the discovery and profile of 8l (ARUK3001185) as a potent, selective, and brain-penetrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease. Crystallographic fragment screening of the Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank inhibition activity, identified 6a and 6b as a pair of outstanding hits. Fragment development of 6 delivered 8l that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in pharmacology screens showed 8l to be selective against serine hydrolases, kinases, and drug targets.

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Section: Resultsmentioning

confidence: 99%

Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit

et al. 2022

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“…The value of these drug-like properties may vary from the drugs of one target to those of another. Therefore, target-specific profiles of drug-like property may be useful for facilitating the analysis of the landscape of drug-like property for targeted therapeutics ( 55 ). As illustrated in Figure 3 , the 2D profiles of the target-specific drug-like properties for those targets in TTD were provided.…”

Section: Collective Profiles Of Drug-like Properties Of Individual Targetmentioning

confidence: 99%

Therapeutic target database update 2022: facilitating drug discovery with enriched comparative data of targeted agents

Zhou

Zhang

Lian

et al. 2021

Nucleic Acids Research

411

241

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Drug discovery relies on the knowledge of not only drugs and targets, but also the comparative agents and targets. These include poor binders and non-binders for developing discovery tools, prodrugs for improved therapeutics, co-targets of therapeutic targets for multi-target strategies and off-target investigations, and the collective structure-activity and drug-likeness landscapes of enhanced drug feature. However, such valuable data are inadequately covered by the available databases. In this study, a major update of the Therapeutic Target Database, previously featured in NAR, was therefore introduced. This update includes (a) 34 861 poor binders and 12 683 non-binders of 1308 targets; (b) 534 prodrug-drug pairs for 121 targets; (c) 1127 co-targets of 672 targets regulated by 642 approved and 624 clinical trial drugs; (d) the collective structure-activity landscapes of 427 262 active agents of 1565 targets; (e) the profiles of drug-like properties of 33 598 agents of 1102 targets. Moreover, a variety of additional data and function are provided, which include the cross-links to the target structure in PDB and AlphaFold, 159 and 1658 newly emerged targets and drugs, and the advanced search function for multi-entry target sequences or drug structures. The database is accessible without login requirement at: https://idrblab.org/ttd/.

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“…For instance, getting the right absorption, distribution, metabolism, and excretion (ADME) properties is crucial for clinical success since undesired pharmacokinetics (PK) and toxicity are the main reasons for clinical failure. There are published guidelines and free tools available to help researchers find the right drug-like space for their candidates (Ritchie et al, 2011;Daina et al, 2017;Jia et al, 2020;Leeson et al, 2021). However, only 17% of the articles reported any calculated physicochemical or ADME descriptors (mostly logP and other rule-of-five descriptors) and <5% presented any experimental ADME data.…”

Section: Quality Of Hitsmentioning

confidence: 99%

Chagas Disease Drug Discovery in Latin America—A Mini Review of Antiparasitic Agents Explored Between 2010 and 2021

et al. 2021

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Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi that endangers almost 70 million people worldwide. The only two drugs that are currently approved for its treatment, benznidazole and nifurtimox, have controversial efficacy in adults and restricting safety issues, leaving thousands of patients without a suitable treatment. The neglect of Chagas disease is further illustrated by the lack of a robust and diverse drug discovery and development portfolio of new chemical entities, and it is of paramount importance to build a strong research and development network for antichagasic drugs. Focusing on drug discovery programs led by scientists based in Latin America, the main endemic region for this disease, we discuss herein what has been published in the last decade in terms of identification of new antiparasitic drugs to treat Chagas disease, shining a spotlight on the origin, chemical diversity, level of characterization of hits, and strategies used for optimization of lead compounds. Finally, we identify strengths and weaknesses in these drug discovery campaigns and highlight the importance of multidisciplinary collaboration and knowledge sharing.

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Target-Based Evaluation of “Drug-Like” Properties and Ligand Efficiencies

Cited by 69 publications

References 112 publications

Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit

Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit

Therapeutic target database update 2022: facilitating drug discovery with enriched comparative data of targeted agents

Chagas Disease Drug Discovery in Latin America—A Mini Review of Antiparasitic Agents Explored Between 2010 and 2021

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