Dynamic Combinatorial Chemistry and Virtual Combinatorial Libraries

Lehn, Jean‐Marie

doi:10.1002/9783906390451.ch8

Cited by 19 publications

(13 citation statements)

References 29 publications

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“…D ynamic combinatorial chemistry (DCC) has added a new dimension to the synthetic capability of combinatorial chemistry by allowing the combinatorial synthesis to occur through reversible covalent reactions [1][2][3]. The benefit of this additional dimension becomes readily evident when dynamic combinatorial libraries (DCLs) are prepared in the presence of a therapeutic target molecule.…”

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Direct screening of a dynamic combinatorial library using mass spectrometry

Poulsen

2006

J. Am. Soc. Mass Spectrom.

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A dynamic combinatorial library (DCL) screening approach is described that permits direct identification of the effective (from ineffective) combination of building blocks in the equilibrating DCL. The approach uses Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) together with sustained off-resonance irradiation collision activated dissociation (SORI-CAD) to detect noncovalent protein-DCL ligand complexes under native conditions. It was shown that in a single, rapid experiment one could concurrently identify all the ligands of interest from the DCL against a background of inactive DCL ligands while still in the presence of the target protein. This result has demonstrated that mass spectrometry may provide a fast preliminary screening approach to identify DCL candidates for later verification with more traditional but time-consuming analysis. The MS/MS enables DCL mixtures to be effectively deconvoluted without the need for either chromatography, synthesis of DCL sub-libraries, conversion of the DCL to a static library, or disruption of the protein-ligand complexes before analysis-all typically necessary for the current screening method for DCLs. ( -3]. The benefit of this additional dimension becomes readily evident when dynamic combinatorial libraries (DCLs) are prepared in the presence of a therapeutic target molecule. The reversible chemistry, together with the target acting as a template, permits self-screening owing to selection and amplification of the "best binders" by molecular recognition events between DCL constituents and the target. There are now multiple examples of ligand discovery from dynamic combinatorial libraries (DCLs) generated in the presence of protein targets [4 -20]. In principle, DCC has the potential to circumvent the need to individually synthesize, characterize, and screen each possible library constituent, however rapid detection of the enriched DCL product(s) still poses a serious analytical problem and is a critical limitation to DCC taking a prominent place in drug discovery [21]. The standard DCL screening approach must carry out the screening of identical DCLs twice-with and without the targetand then compare the equilibrium concentration profiles of all library ligands when generated in both the absence and presence (following disruption of the ligand-target complexes) of target protein [4, 7, 10, 14 -17]-the detection of ligand enrichment in the targeted DCL is the basis of identifying the "best binders". Unfortunately, this screening approach typically necessitates synthesis of individual library components to validate chromatographic (e.g., HPLC) or spectral (e.g., NMR) assignments; this is both labor-and time-intensive and has the effect of undermining the promoted advantages of DCC. The complexity of screening with this indirect method also increases with the size of the DCL owing to chromatographic and/or spectral overlap so that the preparation and screening of DCL sub-libraries becomes necessary for deconvolution of larger DCLs. For DCC to have ...

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confidence: 99%

Direct screening of a dynamic combinatorial library using mass spectrometry

Poulsen

2006

J. Am. Soc. Mass Spectrom.

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“…[4], [11], [12], [16] The promotion of quadruplex DNA formation as observed in solution by NMR coupled with initial biological data, suggests 10 possesses an anticancer activity, which renders this family of compounds worthy of further investigation in terms of both duplex/quadruplex selectivity, bioavailability and expansion of the series to better understand any QSAR that may exist.…”

Section: Discussionmentioning

confidence: 99%

Scope of the Heck Reaction in the Synthesis of a New Family of Anthracene Diacrylamide G-Quadruplex Ligands

Gresley¹,

Abdullah²,

Desai³

et al. 2011

Synthetic Communications

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“…The in vitro evolution of DNA, RNA, and proteins to generate molecules of altered and desired properties has met with considerable success ( [Arnold, 1998;Joyce, 1992;Powell et al, 2001]: the process is ideal for the optimization of protein therapeutic molecules where de novo design is difficult [Vasserot et al, 2003]. The process is now being applied to small molecules by the strategy termed ''Dynamic Combinatorial Chemistry'' [Freemantle, 2002;Klekota and Miller, 1999;Lehn, 1999;Otto et al, 2002]. Dynamic combinatorial chemistry provides for the synthesis of molecules under reversible conditionsFthermodynamic control vs. the kinetic control of conventional combinatorial chemistryFin the presence of a selection mechanism, a template for which some molecules will have enhanced affinity, thus shifting the equilibrium to favor production of this molecular species.…”

Section: Evolutionmentioning

confidence: 99%

Medicines in the 21st century Or pills, politics, potions, and profits: Where is public policy?

Triggle

2003

Drug Development Research

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The delivery of health care over the past century, including drugs for the past 60 years, has brought significant gains to the overall health of the world population. The recent advances in genomics carry the promise, as yet not fulfilled, of far greater benefits perhaps, as far as molecular medicines are concerned of actually delivering Paul Ehrlich's ''magic bullet.'' However, the delivery of currently available health benefits to the world has been remarkably non-uniform and the major fraction of the world's population still remains inadequately served by basic public health services, including clean water and sanitation. Additionally, this same population is devastated by diseases including malaria, tuberculosis, and AIDS. This discrepancy in health care parallels the economic disparities that exist between nations and that are in fact increasing rather than decreasing. The absence of health care is a driving force for the generation and maintenance of poverty. The issue is less science than it is public policy and the will of the rich world to generate the infrastructural environments under which the rewards of science can be shared equitably. The delivery of biomedical science in the future is discussed both in terms of the science that will drive advances and the public policy issues that must be implemented to ensure delivery of scientific benefits. Drug Dev. Res.

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Dynamic Combinatorial Chemistry and Virtual Combinatorial Libraries

Cited by 19 publications

References 29 publications

Direct screening of a dynamic combinatorial library using mass spectrometry

Direct screening of a dynamic combinatorial library using mass spectrometry

Scope of the Heck Reaction in the Synthesis of a New Family of Anthracene Diacrylamide G-Quadruplex Ligands

Medicines in the 21st century Or pills, politics, potions, and profits: Where is public policy?

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