Selection and Amplification of a Catalyst from a Dynamic Combinatorial Library

Self Cite

113

We present a versatile computer model of diverse dynamic combinatorial libraries, and examine how molecular recognition between library members and a template can be used to amplify the best binders. The correlation between host–guest binding and amplification was examined for a set of 50 libraries with >300 components each over a wide range of template and building block concentrations. Depending on these concentrations correlations vary from poor (when using a large excess of template) to good (for very dilute libraries and/or substoichiometric template concentrations), highlighting the need to choose the experimental conditions for dynamic combinatorial libraries thoughtfully.

Section: Methods Of Calculationmentioning

confidence: 86%

Correlation between Host–Guest Binding and Host Amplification in Simulated Dynamic Combinatorial Libraries

Corbett

Otto

Sanders

2004

Self Cite

113

“…Dynamic combinatorial chemistry has spread into many different areas, using an increasing number of reversible reactions to generate not only hosts but also guests for a wide range of targets [3e, 4] as well as sensors, [5] and catalysts. [6] In some cases, spectacular levels of amplification of receptors with exceptionally high affinity [4a] or remarkable structure [7] Abstract: Herein we describe an extensive study of the response of a set of closely related dynamic combinatorial libraries (DCLs) of macrocyclic receptors to the introduction of a focused range of guest molecules. We have determined the amplification of two sets of diastereomeric receptors induced by a series of neutral and cationic guests, including biologically relevant compounds such as acetylcholine and morphine.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Relation between Amplification and Binding in Dynamic Combinatorial Libraries of Macrocyclic Synthetic Receptors in Water

Corbett¹,

Sanders²,

Otto³

2008

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Herein we describe an extensive study of the response of a set of closely related dynamic combinatorial libraries (DCLs) of macrocyclic receptors to the introduction of a focused range of guest molecules. We have determined the amplification of two sets of diastereomeric receptors induced by a series of neutral and cationic guests, including biologically relevant compounds such as acetylcholine and morphine. The host-guest binding affinities were investigated using isothermal titration calorimetry. The resulting dataset enabled a detailed analysis of the relationship between the amplification of selected receptors and host-guest Gibbs binding energies, giving insight into the factors affecting the design, simulation and interpretation of DCL experiments. In particular, two questions were addressed: Is amplification by a given guest selective for the best receptor? And does the best guest induce the largest amplification of a given receptor? Our experimental results and computer simulations showed that the relative levels of amplification of hosts by a guest are well-correlated with their relative affinities, and simulations have confirmed previous observations that amplification can be selective for the best receptor when only modest amounts of guest are used. In contrast, the correlation between guest binding and the extent of amplification of a given receptor across a wide range of guests tends to be poorer, because every guest has its own unique set of affinities for competing receptors in the DCL. This implies that the results of screening a DCL for selective receptors by comparing the response of the mixture to two different guests should be interpreted with caution. DCLs are complex mixtures in which all compounds are connected through a set of equilibria. Obtaining quantitative information about all host-guest binding constants from such systems will require the explicit and simultaneous consideration of all of the main equilibria within a DCL.

“…Starting with some seminal publications by Sanders and co‐workers,5 Lehn and co‐workers,6 and others7 in the mid 1990s, selection experiments with DCLs have now been performed by using various target molecules such as alkali metal ions,8 alkaline‐earth metal ions,9 alkylammonium ions,10 anions,11 N ‐heterocycles,12 crown ethers,13 uracil derivatives,14 halocarbons,15 biphenyl,16 nucleic acids,17 small peptides,18 proteins,19 protein crystals,20 and transition state analogues 21. Compared to this wealth of experimental data, there is a surprising lack of theoretical analyses about the adaptive behavior of DCLs 22.…”

Section: Introductionmentioning

confidence: 99%

The Advantage of Being Virtual—Target‐Induced Adaptation and Selection in Dynamic Combinatorial Libraries

Severin¹

2004

172

Numerical simulations are presented that describe the adaptive behavior of simple dynamic combinatorial libraries (DCLs) upon addition of a target. By studying the effect of various parameters such as the network topology, the initial concentrations, the association constants, and the binding affinities, general characteristics of such systems were derived. It is shown that the adaptation may lead to the amplification of molecules with a high affinity to the target, but only for specific boundary conditions. Furthermore, it is demonstrated that the selection process can be refined by using an evolutionary approach. These results are of importance for the design of selection experiments with DCLs.