Eric J. Martin

Computational approaches for combinatorial library design and molecular diversity analysis.

New approaches for combinatorial library design and molecular diversity analysis have been developed by extending previous work from the fields of quantitative structure-activity relationship, computational chemistry, and chemical information. Recent work has begun to address design efficiency and validation of descriptors for combinatorial library design.

Oriented substituent pharmacophore PRopErtY space (OSPPREYS): a substituent-based calculation that describes combinatorial library products better than the corresponding product-based calculation

Initial combinatorial library designs were based on 2D substituent properties. Subsequently, two important extensions were introduced to improve the approach: use of pharmacophores to introduce 3D information, and performing calculations on the enumerated library products rather than just on the substituents. Unfortunately, practical compromises due to the large number of possible products, the large number of conformations per product, and the explicit dependence on the scaffold limit the application of these extensions in five important ways: (1) to small virtual libraries, (2) to only 3- or 4-point pharmacophores, (3) to inadequate conformational sampling, (4) to simplistic diversity measures, and (5) to requiring a complete new calculation for every new library. The 3D oriented substituent pharmacophores have been developed to overcome these limitations. These add two additional points and corresponding distances to each substituent pharmacophore. This adds little additional computation beyond a normal 3D pharmacophore calculation on the substituents, but recaptures most of the orienting information lost in breaking up the enumerated products into fragments. Two main approximations are still implicitly required: the combinatorial conformer assumption and the template alignment assumption. In turn, however, they are designed to account not just for the 3- and 4-point pharmacophores, but for pharmacophores with up to 9 points in enumerated products with three sites of diversity. Perhaps more importantly, pharmacophore calculations are shown to be very sensitive to conformational sampling. The small number of substituents, plus the small number of rotatable bonds per substituent, permits very thorough conformational sampling. For a rigid scaffold with three diversity sites of 1,000 candidate substituents each, the number of molecules to analyze is reduced by a factor of 10(6), and the number of conformations per molecule is reduced by another 10(4). In addition, the modest number of pairwise substituent similarities permits the creation of a Euclidean property space by MDS. This allows for sophisticated experimental design methods that require coordinates, rather than just the counting of the number of set bits in a library union fingerprint. Finally, oriented substituent calculations are scaffold independent and transferable. They can be stored in a database and need not be repeated for every new library. Thus, there are some approximations in the correspondence between oriented substituent pharmacophore similarities and enumerated product pharmacophore similarities. However, these errors are minor compared to the five advantages that the new method enables: large virtual library sizes, thorough conformational sampling, accounting for 1- to 9-point pharmacophores, creation of a Euclidean property space, and a reusable database of precomputed substituent values.

Using Peptoid Libraries [Oligo N-Substituted Glycines] for Drug Discovery

Publisher Summary This chapter explores the use of peptoid libraries ‘oligo n -substituted glycines’ for drug discovery. A series of compounds for solid-phase synthesis have been prepared with functional groups similar to or identical to the natural amino acids. In general, either reductive amination, route A, or alkylation, route B, provide the necessary monomers. They are then incorporated into a growing peptide/peptoid chain using the activating agents BOP or PyBroP under conditions similar to the Merrifield approach to peptide synthesis. Yields and characteristics of the products are analogous to those of peptides. Oligomeric N substituted glycines (NSG) peptoids and peptide/peptoid chimeras have been prepared with activity in several different bioassays. Synthesis can also be accomplished using a different scheme. The NSG oligomer can be thought of as an alternating copolymer of acetate/amine units rather than an oligomer of NSG units. The submonomers can be sequentially reacted to give a growing peptoid chain identical to that synthesized by traditional Merrifield methods.