Lead Generation Based on Compound Collection Screening

Weigelt, Dirk; Dorange, Ismet

doi:10.1002/9783527677047.ch05

Cited by 4 publications

(4 citation statements)

References 168 publications

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“…One of the most important decisions a drug discovery team can make is the choice of lead generation strategy to identify chemical starting points. − Traditional lead generation strategies have been random high throughput screening (HTS), fragment-based lead generation (FBLG), structure-based drug design (SBDD), utilization of known literature such as fast-follower or knowledge-based programs, and more recently DNA-encoded library screening (DEL) . The choice of which strategy to employ is dependent on multiple factors such as the technical demands for each approach, overall costs, and access to appropriate screening libraries or chemical starting points for each technology.…”

Section: Introductionmentioning

confidence: 99%

Where Do Recent Small Molecule Clinical Development Candidates Come From?

2018

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An analysis of 66 published clinical candidates from Journal of Medicinal Chemistry has been conducted to shed light on which lead generation strategies are most frequently employed in identifying drug candidates. The most frequent lead generation strategy (producing a drug candidate) was based on starting points derived from previously known compounds (43%) followed by random high throughput screening (29%). The remainder of approaches included focused screening, structure-based drug design (SBDD), fragment-based lead generation (FBLG), and DNA-encoded library screening (DEL). An analysis of physicochemical properties on the hit-to-clinical pairs shows an average increase in molecular weight (ΔMW = +85) but no change in lipophilicity (ΔclogP = -0.2), although exceptions are noted. The majority (>50%) of clinical candidates were found to be structurally very different from their starting point and were more complex. Finally, several reports of noncovalent scaffolds modified by a covalent warhead using SBDD approaches are discussed.

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Section: Introductionmentioning

confidence: 99%

Where Do Recent Small Molecule Clinical Development Candidates Come From?

2018

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“…A whole paragraph of a book chapter [261] on the issue of generating new compounds for screening, which somehow echoes with the last quote above, should be mentioned here: "There is a common misconception that "novel" compounds or concepts will lead to dramatically different structural features. It is unlikely that the drug of the future will be built from radically other structural classes than today's drugs.…”

Section: Provide Pertinent Series Of New Chemical Entities To Chemica...mentioning

confidence: 92%

On drug discovery against infectious diseases and academic medicinal chemistry contributions

Janin¹

2022

Beilstein J. Org. Chem.

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This perspective is an attempt to document the problems that medicinal chemists are facing in drug discovery. It is also trying to identify relevant/possible, research areas in which academics can have an impact and should thus be the subject of grant calls. Accordingly, it describes how hit discovery happens, how compounds to be screened are selected from available chemicals and the possible reasons for the recurrent paucity of useful/exploitable results reported. This is followed by the successful hit to lead stories leading to recent and original antibacterials which are, or about to be, used in human medicine. Then, illustrated considerations and suggestions are made on the possible inputs of academic medicinal chemists. This starts with the observation that discovering a “good” hit in the course of a screening campaign still rely on a lot of luck – which is within the reach of academics –, that the hit to lead process requires a lot of chemistry and that if public–private partnerships can be important throughout these stages, they are absolute requirements for clinical trials. Concerning suggestions to improve the current hit success rate, one academic input in organic chemistry would be to identify new and pertinent chemical space, design synthetic accesses to reach these and prepare the corresponding chemical libraries. Concerning hit to lead programs on a given target, if no new hits are available, previously reported leads along with new structural data can be pertinent starting points to design, prepare and assay original analogues. In conclusion, this text is an actual plea illustrating that, in many countries, academic research in medicinal chemistry should be more funded, especially in the therapeutic area neglected by the industry. At the least, such funds would provide the intensive to secure series of hopefully relevant chemical entities which appears to often lack when considering the results of academic as well as industrial screening campaigns.

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“…“patent-busting”. High-throughput screening (HTS) was the most productive form of screening, , accounting for the majority of screening-derived lead series in most years, while Focused Screening , and Fragment Screening were also well-represented. DEL screening , emerged as a source of leads in the last 5 years.…”

Section: Introductionmentioning

confidence: 99%

Screening Ultra-Large Encoded Compound Libraries Leads to Novel Protein–Ligand Interactions and High Selectivity

Collie,

Clark,

Keefe

et al. 2024

J. Med. Chem.

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The DNA-encoded library (DEL) discovery platform has emerged as a powerful technology for hit identification in recent years. It has become one of the major parallel workstreams for small molecule drug discovery along with other strategies such as HTS and data mining. For many researchers working in the DEL field, it has become increasingly evident that many hits and leads discovered via DEL screening bind to target proteins with unique and unprecedented binding modes. This Perspective is our attempt to analyze reports of DEL screening with the purpose of providing a rigorous and useful account of the binding modes observed for DEL-derived ligands with a focus on binding mode novelty. ■ SIGNIFICANCEScreening DNA-encoded libraries (DELs) of small molecules has recently become one of the main technologies employed for discovering potential new drugs. Here, we analyze and discuss recent published DEL screens performed against important clinical molecular targets. Notable trends observed, including an apparent tendency for inhibitors from DEL screens to be highly selective and to adopt novel binding modes, are highlighted and discussed alongside the current state of the field and future considerations.

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Lead Generation Based on Compound Collection Screening

Cited by 4 publications

References 168 publications

Where Do Recent Small Molecule Clinical Development Candidates Come From?

Where Do Recent Small Molecule Clinical Development Candidates Come From?

On drug discovery against infectious diseases and academic medicinal chemistry contributions

Screening Ultra-Large Encoded Compound Libraries Leads to Novel Protein–Ligand Interactions and High Selectivity

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