Combinatorial Chemistry Review

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Kaiser Test
Analytical method for the determination of primary amines. Particularly useful for resin-bound analysis as the chromophoric product is released into solution allowing quantitation by colorimetry.

Knorr Resin
Amide-releasing, acid-cleavable solid support.

Ladder Synthesis
Strategy for library assembly where a portion of compound is capped following incorporation of each building block, such that the final sample comprises a mixture of all possible truncated products. This may be designed such that approximately equimolar quantities of each truncated form are present as an approach to gain maximal diversity, or such that each truncate is present in a small amount relative to the fully elaborated product. In the latter case, analysis of the pattern of products serves to identify the parent and is termed ladder encoding.

Lead Compound
A compound that exhibits pharmacological properties which suggest its value as a starting point for drug development.

Lead Discovery
The process of identifying active new chemical entities, which by subsequent modification may be transformed into a clinically useful drug.

Lead Generation
The term applied to strategies developed to identify compounds which possess a desired but non-optimized biological activity.

Lead Optimization
The synthetic modification of a biologically active compound, to fulfill stereo electronic, physicochemical, pharmacokinetic and toxicological clinical usefulness.

Libraries from Libraries
Strategy for accelerating library production, whereby an existing library is subjected to a relatively minor modification in order to generate a new library, thus avoiding the majority of chemical development and rehearsal required for a new library.

Library Equivalent
The number of samples which equals the number of compounds in the library. Particularly applied to libraries in which individual beads are encoded, where one library equivalent is the number of beads which equals the number of compounds in the library.

Bifunctional chemical moiety attaching a compound to a solid support or soluble support which can be cleaved to release compounds from the support. A careful choice of linker allows cleavage to be performed under appropriate conditions compatible with the stability of the compound and assay method.

A small molecule that binds specifically to a larger one; for example, a hormone is the ligand for its specific protein receptor.

Ligand Design
The design of ligands using structural information about the target to which they should bind, often by attempting to maximize the energy of the interaction.

Water-insoluble molecule which is soluble in nonpolar solvents such as ether. Divided into two classes: Saponifiable and nonsaponifiable.

Capable of combining with or dissolving in lipids.

The affinity of a molecule or a moiety for a lipophilic environment. It is commonly measured by its distribution behavior in a biphasic system, either liquid-liquid (e.g., partition coefficient in 1-octanol/water) or solid/liquid (retention on reversed-phase high performance liquid chromatography (RP-HPLC) or thin-layer chromatography (TLC) system).

Lipinski's Rule of 5
Set of criteria for predicting the oral bioavailability of a compound on the basis of simple molecular features ( MolWt <= 500, clogp <= 5.0, Hbond donors <= 5, Hbond acceptors <=5, Free-rotation bonds <= 10). Often used to profile a library or virtual library with respect to the proportion of drug - like members which it contains. An algorithm, developed by Christopher A. Lipinski (of Pfizer) and colleagues, in which many of the cutoff numbers are five or multiples of five. There are actually four rules, and Pfizer has developed a additional number of criteria for adoption of lead candidates.

Liquid Phase Chemistry
Synthetic process employing a macromolecular soluble support.

Characteristic property of a solid support which describes the amount of a specific chemical species per unit mass of the support.