Natural product-like chemical space: search for chemical dissectors of macromolecular interactions

Reayi, Ayub; Arya, Prabhat

doi:10.1016/j.cbpa.2005.04.007

Cited by 91 publications

(60 citation statements)

References 39 publications

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“…Adrenosterone (2), as teroid hormone produced in the adrenal cortex of mammals,c ontains five contiguous stereogenic centers.F our of the carbocyclic rings of 2 are functionalized with an enone or ketone.These key functional groups provide synthetic handles to transform 2 into as et of diverse frameworks in few synthesis steps.Byexploiting ringexpansion processes,n amely aS chmidt reaction and aB V oxidation, and selective ring-opening reactions,f ive distinct and complex scaffolds (11)(12)(13)(14)(15)w ith functional groups for further modifications were generated (Scheme 1c).…”

Section: Creating Diversity Based On Natural Product Scaffoldsmentioning

confidence: 99%

“…[11] Theq uality of compound libraries thus began to gain attention. [12] Thefocus of synthetic chemists moved to the diversity and complexity of the core structures or scaffolds present within acompound collection. [13] Thes caffold is the core molecular framework that provides the basic shape,r igidity,o rf lexibility of am olecule, [14] and exposes various substituents over its periphery in…”

Section: Introductionmentioning

confidence: 99%

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Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

et al. 2016

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Scaffold diversity is a crucial feature of compound collections that has a huge impact on their success in biological screenings. The synthesis of highly complex and diverse scaffolds, which could be based on natural products, for example, is an arduous task that requires expertise in various aspects of organic synthesis and structural analysis. This challenge has been addressed by a number of synthesis designs, which employ natural products as a source of scaffold diversity, transform suitably designed common intermediates into various molecular frameworks, or entail highly concise synthetic routes to a number of distinct and complex scaffolds. In this Minireview, we highlight recent synthetic developments towards the construction of diverse and complex scaffolds and the application of the resulting compound collections in drug and probe discovery.

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Section: Creating Diversity Based On Natural Product Scaffoldsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

et al. 2016

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“…Traditionally viewed as exceedingly difficult, recent breakthroughs have provided a template for the development of low molecular weight, "drug-like" inhibitors (for reviews see: [7][8][9][10][11][12]). A key insight was made by the Wells group when they observed that protein-protein interactions often contain "hot spots" on their surfaces [13][14][15].…”

Section: Inhibitors Of Protein-protein Interac-tionsmentioning

confidence: 99%

Chemical Control Over Protein-Protein Interactions: Beyond Inhibitors

Gestwicki¹,

Marinec²

2007

CCHTS

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Protein-protein interactions have become attractive drug targets and recent studies suggest that these interfaces may be amenable to inhibition by small molecules. However, blocking specific interactions may not be the only way of manipulating the extensive network of interacting proteins. Recently, several approaches have emerged for promoting these interactions rather than inhibiting them. Typically, these strategies employ a bifunctional ligand to simultaneously bind two targets, forcing their juxtaposition. Chemically "riveting" specific protein contacts can reveal important aspects of regulation, such as the consequences of stable dimerization or the effects of prolonged dwell time. Moreover, in some cases, entirely new functions arise when two proteins, which normally do not interact, are brought into close proximity with one another. Together with inhibitors, bifunctional molecules are part of a growing toolbox of chemical probes that can be used to reversibly and selectively control the interact-ome. Using these reagents, new insights into the dynamics of protein-protein interactions and their importance in biology are beginning to emerge. Future hurdles in this area lie in the development of robust synthetic platforms for rapidly generating compounds to meet the challenges of diverse protein-protein interfaces.

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“…It is also desirable that combinatorial libraries become enriched with "druglike" elements, such as a higher degree of chirality and rigidity, seen in libraries of natural products. Several successful attempts to address the shortcomings of combinatorial chemistry libraries by developing synthetic libraries of natural-like compounds have been reported [29,30]. We anticipate that the current shift in combinatorial chemistry libraries away from numerically large to more focused, target-oriented libraries will continue in the near future and that these libraries will be helpful in developing ligands with improved binding characteristics.…”

Section: Library-based Approachesmentioning

confidence: 99%