Best practices for repurposing studies

Lewis, Richard A.

doi:10.1007/s10822-021-00430-5

Cited by 6 publications

(8 citation statements)

References 23 publications

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“…Hit compounds tend to exhibit a certain level of molecular complexity and need to be significantly modified to progress the campaigns. Another major limitation is an unsatisfactory and nonexhaustive coverage of chemical space . To remedy these shortcomings, virtual preassessment via molecular docking studies can be a resource-saving method to filter for most promising binding candidates.…”

Section: Introductionmentioning

confidence: 99%

“…Another major limitation is an unsatisfactory and nonexhaustive coverage of chemical space. 2 To remedy these shortcomings, virtual preassessment via molecular docking studies can be a resource-saving method to filter for most promising binding candidates. The latest reports feature the screening of billion-sized chemical spaces by utilizing a workaround to handle such tremendous numbers whereby only the small building blocks are docked into the binding site and assessed for their interactions with the target.…”

Section: ■ Introductionmentioning

confidence: 99%

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Magnet for the Needle in Haystack: “Crystal Structure First” Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces

Müller

Klein²,

Tarkhanova

et al. 2022

J. Med. Chem.

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Fragment-based drug discovery (FBDD) has successfully led to approved therapeutics for challenging and "undruggable" targets. In the context of FBDD, we introduce a novel, multidisciplinary method to identify active molecules from purchasable chemical space. Starting from four small-molecule fragment complexes of protein kinase A (PKA), a template-based docking screen using Enamine's multibillion REAL Space was performed. A total of 93 molecules out of 106 selected compounds were successfully synthesized. Forty compounds were active in at least one validation assay with the most active follow-up having a 13,500-fold gain in affinity. Crystal structures for six of the most promising binders were rapidly obtained, verifying the binding mode. The overall success rate for this novel fragment-to-hit approach was 40%, accomplished in only 9 weeks. The results challenge the established fragment prescreening paradigm since the standard industrial filters for fragment hit identification in a thermal shift assay would have missed the initial fragments.

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Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Magnet for the Needle in Haystack: “Crystal Structure First” Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces

Müller

Klein²,

Tarkhanova

et al. 2022

J. Med. Chem.

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show abstract

“…One holy grail of computational chemists is to repurpose existing drugs proposed by structure-based experiments. Although this pursuit appears at best hardly probable due to the optimization of drugs for their on-targets [ 157 , 158 ], we believe that binding site comparisons are the most useful in finding not global but local similarities, and therefore to repurpose fragments [ 22 ] and not full ligands, provided that the selected fragments can be grown or linked to enumerate full ligands or target-focused libraries [ 170 ].…”

Section: Discussionmentioning

confidence: 99%

“…The best possible validation method of any binding site comparison tool is indeed to experiment. True prospective validations ( Table 5 ) are still rare for several reasons: Fragment/ligand promiscuity towards unrelated targets of known 3D structure remains are a rare event [ 156 ]; Direct drug repurposing from in silico [ 157 ] or in vitro screening strategies have not yet yielded any success in terms of new indication approvals [ 158 ], as recently exemplified by the COVID-19 pandemic; The experimental validation of putative binding site similarities is not as straightforward as testing many compounds on a single target. For every putative off-target, a suitable assay has to be used if available, or more likely needs to be developed on purpose.…”

Section: Prospective Applicationsmentioning

confidence: 99%

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Estimating the Similarity between Protein Pockets

Eguida

Rognan

2022

IJMS

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With the exponential increase in publicly available protein structures, the comparison of protein binding sites naturally emerged as a scientific topic to explain observations or generate hypotheses for ligand design, notably to predict ligand selectivity for on- and off-targets, explain polypharmacology, and design target-focused libraries. The current review summarizes the state-of-the-art computational methods applied to pocket detection and comparison as well as structural druggability estimates. The major strengths and weaknesses of current pocket descriptors, alignment methods, and similarity search algorithms are presented. Lastly, an exhaustive survey of both retrospective and prospective applications in diverse medicinal chemistry scenarios illustrates the capability of the existing methods and the hurdle that still needs to be overcome for more accurate predictions.

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Exploring DrugCentral: from molecular structures to clinical effects

Halip,

Avram,

Curpan

et al. 2023

J Comput Aided Mol Des

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DrugCentral, accessible at https://drugcentral.org, is an open-access online drug information repository. It covers over 4950 drugs, incorporating structural, physicochemical, and pharmacological details to support drug discovery, development, and repositioning. With around 20,000 bioactivity data points, manual curation enhances information from several major digital sources. Approximately 724 mechanism-of-action (MoA) targets offer updated drug target insights. The platform captures clinical data: over 14,300 on- and off-label uses, 27,000 contraindications, and around 340,000 adverse drug events from pharmacovigilance reports. DrugCentral encompasses information from molecular structures to marketed formulations, providing a comprehensive pharmaceutical reference. Users can easily navigate basic drug information and key features, making DrugCentral a versatile, unique resource. Furthermore, we present a use-case example where we utilize experimentally determined data from DrugCentral to support drug repurposing. A minimum activity threshold t should be considered against novel targets to repurpose a drug. Analyzing 1156 bioactivities for human MoA targets suggests a general threshold of 1 µM: t = 6 when expressed as − log[Activity(M)]). This applies to 87% of the drugs. Moreover, t can be refined empirically based on water solubility (S): t = 3 − logS, for logS < − 3. Alongside the drug repurposing classification scheme, which considers intellectual property rights, market exclusivity protections, and market accessibility, DrugCentral provides valuable data to prioritize candidates for drug repurposing programs efficiently.

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Best practices for repurposing studies

Cited by 6 publications

References 23 publications

Magnet for the Needle in Haystack: “Crystal Structure First” Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces

Magnet for the Needle in Haystack: “Crystal Structure First” Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces

Estimating the Similarity between Protein Pockets

Exploring DrugCentral: from molecular structures to clinical effects

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