Competitive Intelligence–based Lead Generation and Fast Follower Approaches

Yu, Jinhui; Liu, Ziping; Holenz, Jörg; Yang, Huanyu

doi:10.1002/9783527677047.ch08

Cited by 5 publications

(6 citation statements)

References 128 publications

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“…Followon drugs or "fast-follower" type approaches have been a staple in the pharmaceutical industry. 7 Many successful follow-on drugs have come to the market, one-third of which surprisingly receive priority review from the FDA, thus indicating that many follow-on drugs are potential "best-in-class" options. 121 A fast-follower type approach often seeks to identify the minimal changes that provide both differentiation and opportunities to claim novelty and invention.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…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%

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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: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Where Do Recent Small Molecule Clinical Development Candidates Come From?

2018

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“…Even though resistance to fluoroquinolones among clinical isolates was detected relatively quickly after their introduction [ 7 ], bacterial topoisomerases still remain clinically validated targets due to their conservation across all bacteria and also their strong structural differences to eukaryotic topoisomerases [ 8 , 9 , 10 , 11 , 12 ]. Moreover, because of the structural similarities between DNA gyrase and topoisomerase IV, dual targeting is possible, which prolongs the onset of resistance [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Thiosemicarbazide Derivatives Decrease the ATPase Activity of Staphylococcus aureus Topoisomerase IV, Inhibit Mycobacterial Growth, and Affect Replication in Mycobacterium smegmatis

Kowalczyk

Paneth

Trojanowski

et al. 2021

IJMS

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Compounds targeting bacterial topoisomerases are of interest for the development of antibacterial agents. Our previous studies culminated in the synthesis and characterization of small-molecular weight thiosemicarbazides as the initial prototypes of a novel class of gyrase and topoisomerase IV inhibitors. To expand these findings with further details on the mode of action of the most potent compounds, enzymatic studies combined with a molecular docking approach were carried out, the results of which are presented herein. The biochemical assay for 1-(indol-2-oyl)-4-(4-nitrophenyl) thiosemicarbazide (4) and 4-benzoyl-1-(indol-2-oyl) thiosemicarbazide (7), showing strong inhibitory activity against Staphylococcus aureus topoisomerase IV, confirmed that these compounds reduce the ability of the ParE subunit to hydrolyze ATP rather than act by stabilizing the cleavage complex. Compound 7 showed better antibacterial activity than compound 4 against clinical strains of S. aureus and representatives of the Mycobacterium genus. In vivo studies using time-lapse microfluidic microscopy, which allowed for the monitoring of fluorescently labelled replisomes, revealed that compound 7 caused an extension of the replication process duration in Mycobacterium smegmatis, as well as the growth arrest of bacterial cells. Despite some similarities to the mechanism of action of novobiocin, these compounds show additional, unique properties, and can thus be considered a novel group of inhibitors of the ATPase activity of bacterial type IIA topoisomerases.

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“…In practice, this translates to novel chemical series with new features to differentiate from already known chemical space. For example, bioisosteric replacement and scaffold hopping [50], [51] are used for lead optimisation or to access back-up or a new lead series whereas fast follower approaches aim to escape public or patent protected chemical space [52], [53]. For that reason we examine the high scoring and high populated BM clusters but this time with the lowest SNN similarity values.…”

Section: Visual Inspectionmentioning

confidence: 99%

De Novo Design with Deep Generative Models Based on 3D Similarity Scoring

Papadopoulos¹,

Giblin²,

Janet³

et al. 2021

Preprint

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<p>We have demonstrated the utility of a 3D shape and pharmacophore similarity scoring component in molecular design with a deep generative model trained with reinforcement learning. Using Dopamine receptor type 2 (DRD2) as an example and its antagonist haloperidol <b>1</b> as a starting point in a ligand based design context, we have shown in a retrospective study that a 3D similarity enabled generative model can discover new leads in the absence of any other information. It can be efficiently used for scaffold hopping and generation of novel series. 3D similarity based models were compared against 2D QSAR based, indicating a significant degree of orthogonality of the generated outputs and with the former having a more diverse output. In addition, when the two scoring components are combined together for training of the generative model, it results in more efficient exploration of desirable chemical space compared to the individual components. </p>

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Competitive Intelligence–based Lead Generation and Fast Follower Approaches

Cited by 5 publications

References 128 publications

Where Do Recent Small Molecule Clinical Development Candidates Come From?

Where Do Recent Small Molecule Clinical Development Candidates Come From?

Thiosemicarbazide Derivatives Decrease the ATPase Activity of Staphylococcus aureus Topoisomerase IV, Inhibit Mycobacterial Growth, and Affect Replication in Mycobacterium smegmatis

De Novo Design with Deep Generative Models Based on 3D Similarity Scoring

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