Are Target-Family-Privileged Substructures Truly Privileged?

Abstract

One of the early and effective approaches to G-coupled protein receptor target family library design was the analysis of a set of ligands for frequently occurring chemical moieties or substructures. Various methods ranging from frameworks analysis to pharmacophores have been employed to find these so-called target-family-privileged substructures. Although the use of these substructures is common practice in combinatorial library design and has produced leads, the methods used for finding them rarely verified their selectivity for the particular target family from which they were derived. The frequency of occurrence among ligands associated with a target receptor family is not a sufficient criterion for those substructures to receive the label of target-family-privileged substructure. This study explores the question of selectivity of ClassPharmer generated fragments for a series of target families: GPCRs, nuclear hormone receptors, serine proteases, protein kinases, and ligand-gated ion channels. In addition, a GPCR focused library and a random set of 10k compounds are examined in terms of their target-family-privileged-substructure composition. The results challenge the combinatorial chemistry concept of target-family-privileged substructures and suggest that many of these fragments may simply be drug-like or attractive for various receptors in accordance with the original definition of privileged substructures.

Design of chemical libraries with potentially bioactive molecules applying a maximum common substructure concept

“…These substructures are often used to build up target familyselective screening libraries. Schnur et al performed a substructure analysis of ligand sets from five different target families and examined the occurrence of potential privileged substructures [19]. They found a remarkable promiscuity of the substructures and concluded that most of these substructures might be better described as drug-like and not as target family specific.…”

Exploring Target-Selectivity Patterns of Molecular Scaffolds

“…In many instances, substructures considered to be target class-selective on the basis of frequency of occurrence analysis have also been detected in compounds active against other target families; 2 hence, the existence of truly privileged structural motifs has been controversial. 2 Recently, we have carried out a large-scale analysis of public domain compound data to investigate whether target class-selective molecular scaffolds exist.…”

“…In many instances, substructures considered to be target class-selective on the basis of frequency of occurrence analysis have also been detected in compounds active against other target families; 2 hence, the existence of truly privileged structural motifs has been controversial. 2 Recently, we have carried out a large-scale analysis of public domain compound data to investigate whether target class-selective molecular scaffolds exist. 3 To avoid potential caveats of occurrence frequency-based analysis, we searched for compounds with multiple activity annotations and formed pairs of biological targets that were "connected" by at least five active compounds.…”

Medicinal Chemistry Approaches to Design of Drug Prototypes

“…9 As tecnologias vigentes, no entanto, proporcionam metodologias avaliativas baseadas em bibliotecas oriundas de química combinatória, o que implica na identificação precoce de fragmentos estruturais que poderiam resultar na promiscuidade de protótipos. 27 Esses fragmentos, porém, sob outra perspectiva, receberam a original denominação de "estrutura privilegiada", termo formulado por Evans e Patchett, que corresponde à estrutura mínima presente em diversos compostos protótipos de fármacos capazes de interagir com mais de um tipo de biorreceptor. 4,28,29 Este conceito tomou um significado além da original concepção de Evans, ao ser correlacionado a uma estrutura mínima seletiva para uma família de receptores.…”

“…4,28,29 Este conceito tomou um significado além da original concepção de Evans, ao ser correlacionado a uma estrutura mínima seletiva para uma família de receptores. 27 Entretanto, a identificação de uma estrutura privilegiada consiste em um grande desafio e não pode estar simplesmente correlacionada à frequência de ocorrência de certas subunidades em coleções de moléculas bioativas, pois necessitam de estudos criteriosos que confirmem a importância das subunidades para interação fármaco-receptor. 27 Não obstante, a seletividade de um fragmento por uma família de receptores não é de fácil atribuição, o que ressalta a importância do desenho sob medida de moléculas para a determinação de estruturas privilegiadas segundo avaliações das relações estruturaatividade.…”