Chemical name to structure: OPSIN, an open source solution.

We have produced an open source, freely available, algorithm (Open Parser for Systematic IUPAC Nomenclature, OPSIN) that interprets the majority of organic chemical nomenclature in a fast and precise manner. This has been achieved using an approach based on a regular grammar. This grammar is used to guide tokenization, a potentially difficult problem in chemical names. From the parsed chemical name, an XML parse tree is constructed that is operated on in a stepwise manner until the structure has been reconstructed from the name. Results from OPSIN on various computer generated name/structure pair sets are presented. These show exceptionally high precision (99.8%+) and, when using general organic chemical nomenclature, high recall (98.7-99.2%). This software can serve as the basis for future open source developments of chemical name interpretation.

Dynamic combinatorial discovery of a [2]-catenane and its guest-induced conversion into a molecular square host.

A simple water-soluble naphthalenedithiol building block is converted quantitatively into a series of octameric [2]-catenanes, composed of two interlocked molecular squares. When this mixture is re-equilibrated in the presence of an adamantyl ammonium guest, the catenanes disassemble into their macrocyclic components that bind the guest with nanomolar affinity in water.

Exploring the relation between amplification and binding in dynamic combinatorial libraries of macrocyclic synthetic receptors in water.

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.

Competition between receptors in dynamic combinatorial libraries: amplification of the fittest?

Dynamic combinatorial chemistry is a powerful tool for the discovery of strong binders (synthetic receptors or ligands) because binding causes a shift in the equilibrium of library members toward those that bind well. Ideally, the best binders are selectively amplified. However, theoretical studies predict this is not always the case. This paper describes the first quantitative experimental evidence proving that, under special circumstances, the preferential amplification of suboptimal synthetic receptors can indeed occur. Our results also demonstrate that reducing the amount of guest in the library can rectify such undesirable behavior and ensures selective amplification of the fittest receptor.

Diastereoselective amplification of an induced-fit receptor from a dynamic combinatorial library.

A high-affinity, induced-fit receptor for NMe4I was discovered using dynamic combinatorial chemistry. The addition of the guest to a dynamic combinatorial library made using a racemic mixture of chiral building blocks caused the strong and highly diastereoselective amplification of the receptor at the expense of other library components. The receptor and its mode of binding were characterized by NMR, ITC, and re-equilibration experiments, from which it was deduced that the receptor probably forms a folded four-stave barrel shape on binding of the guest.

Correlation between host-guest binding and host amplification in simulated dynamic combinatorial libraries.

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.

What are the limits to the size of effective dynamic combinatorial libraries?

Using simple computer simulations of model dynamic combinatorial libraries, we show that the best binders can be amplified to useful concentrations in libraries containing 10-10(6) compounds. [structure: see text]