Ligand specificity, privileged substructures and protein druggability from fragment-based screening

Barelier, Sarah; Krimm, Isabelle

doi:10.1016/j.cbpa.2011.02.020

Cited by 48 publications

(50 citation statements)

References 43 publications

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“…71,72,73,74 It was also found that less polar fragments tend to bind with lower affinity and more promiscuously. 29,56,75 It seems that the presence of a strong hydrogen bond in the initial fragment indicates that a strong anchor point is likely to be maintained. 64 If the fragment does shift, it likely had multiple orientations in the first place, possibly disguised in poorly defined electron density.…”

Section: Size and Shape Considerationsmentioning

confidence: 99%

“…75,89,91 Some targets, such as many enzymes, have a well-defined pocket that has evolved to bind small molecules, so it is not surprising that many fragments bind in these substrate binding sites, often making some of the same interactions as the natural substrates. For example, screens against kinases often yield fragments that bind in the adenosine binding site, and these often have high ligand efficiency values.…”

Section: Target Related Aspectsmentioning

confidence: 99%

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Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia

et al. 2016

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Fragment-based drug discovery (FBDD) is well suited for discovering both drug leads and chemical probes of protein function: it can cover broad swaths of chemical space and allows the use of creative chemistry. FBDD is widely implemented for lead discovery in industry, but is sometimes used less systematically in academia. Design principles and implementation approaches for fragment libraries are continually evolving, and the lack of up-to-date guidance may prevent more effective application of FBDD in academia. This Perspective explores many of the theoretical, practical, and strategic considerations that occur within FBDD programs, including the optimal size, complexity, physicochemical profile, and shape profile of fragments in FBDD libraries, as well as compound storage, evaluation, and screening technologies. This compilation of industry experience in FBDD will hopefully be useful for those pursuing FBDD in academia.Rules are for the obedience of fools and the guidance of wise men.Harry Day, Royal Air Force (1898-1977

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Section: Size and Shape Considerationsmentioning

confidence: 99%

Section: Target Related Aspectsmentioning

confidence: 99%

Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia

et al. 2016

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“…Les fragments qui apparaissent comme touches dans les expériences de criblage sont ensuite validés un par un par différentes approches RMN (Figure 4). La RMN présente aussi l'avantage d'être une méthode structurale, ce qui nous permet non seulement de cribler les fragments, mais aussi d'intervenir dans la sélection des fragments touches, dans leur optimisation et leur évolution en molécules « tête de série », en s'aidant de données structurales concernant le complexe protéine-fragment [19][20][21][22][23][24][25].…”

Section: Conception Rationnelle Assistée Par La Résolution Des Structunclassified

Le criblage de fragments

Krimm

2015

Med Sci (Paris)

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> Le criblage de molécules fragments a obtenu un succès incontestable ces dix dernières années pour la conception de médicaments et apparaît aujourd'hui comme une des voies incontournables pour générer des candidats dans le cas de cibles thérapeutiques ambitieuses et difficiles. Dans cette revue, les principaux concepts et les raisons du succès de la méthode des fragments sont rappelés, et les techniques et stratégies utilisées dans cette approche sont discutées. > octanol/eau logP inférieur à 3 1 , et un nombre de donneurs ainsi que d'accepteurs de liaisons hydrogène inférieur à 3. D'autres paramètres physicochimiques ont aussi été proposés par la suite, tels que la surface polaire des molécules, correspondant à la surface des atomes polaires (azote, oxygène, etc.), une valeur reliée à la capacité des molécules à pénétrer dans les cellules. La tendance actuelle est de considérer une masse moléculaire inférieure à 250 g/mol et une solubilité dans l'eau > 500 M comme les caracté-ristiques principales des fragments. Ces molécules fragments vont être criblées contre une cible thérapeu-tique choisie dans le cadre d'une pathologie particulière, ce qui permet d'identifier un certain nombre de fragments dits « points de départ » possibles, qui seront ensuite transformés en candidats médicaments. En raison de leur simplicité, ces molécules fragments ont généralement une affinité faible envers la cible protéique, c'est-à-dire une constante de dissociation du complexe protéine-fragment K D > 10-1 000 M. Dans la majorité des cas, aucune activité n'est détectable, et seules des mesures biophysiques permettent de s'assurer de l'interaction du fragment avec la protéine cible. L'enjeu de l'approche consiste alors à transformer le fragment initial (point de départ) en un candidat médicament qui pourra être testé en phase clinique, selon un processus rationnel et itératif s'appuyant sur des données structurales du complexe protéine-molécule. Les raisons du succès de la méthode des fragments sont multiples, et les avancées récentes obtenues en oncologie et en neurologie ( maladie 1 Logarithme du rapport des concentrations de la molécule étudiée dans l'octanol et dans l'eau, logP = log (C oct /C eau ).

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“…The approval of the B‐Raf kinase inhibitor vemurafenib (Zelboraf) in 20112 and the Bcl‐2 inhibitor venetoclax (Venclexta) in 2016,3 coupled with the ongoing evaluation of over 20 candidates in clinical trials,4 validates this approach as a complementary strategy to other hit‐discovery techniques such as high‐throughput screening 5. While the growing prevalence of fragment‐based approaches is encouraging, evaluation of many existing fragment libraries shows a predominance of (hetero)aromatic, “flat” compounds, with a deficiency of chiral, sp 3 ‐rich examples 6, 7…”

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confidence: 98%

Partially Saturated Bicyclic Heteroaromatics as an sp³‐Enriched Fragment Collection

et al. 2016

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Fragment‐based lead generation has proven to be an effective means of identifying high‐quality lead compounds for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp2‐rich aromatic compounds, which limits the structural (and hence biological) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp3 character. Subsequent derivatization led to a fragment collection featuring regio‐ and stereo‐controlled introduction of substituents on the saturated ring system, often with formation of new stereocenters.

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Ligand specificity, privileged substructures and protein druggability from fragment-based screening

Cited by 48 publications

References 43 publications

Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia

Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia

Le criblage de fragments

Partially Saturated Bicyclic Heteroaromatics as an sp³‐Enriched Fragment Collection

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Ligand specificity, privileged substructures and protein druggability from fragment-based screening

Cited by 48 publications

References 43 publications

Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia

Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia

Le criblage de fragments

Partially Saturated Bicyclic Heteroaromatics as an sp3‐Enriched Fragment Collection

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Partially Saturated Bicyclic Heteroaromatics as an sp³‐Enriched Fragment Collection