Property Distributions:  Differences between Drugs, Natural Products, and Molecules from Combinatorial Chemistry

Abstract

The differences between three different compound classes, natural products, molecules from combinatorial synthesis, and drug molecules, were investigated. The major structural differences between natural and combinatorial compounds originate mainly from properties introduced to make combinatorial synthesis more efficient. These include the number of chiral centers, the prevalence of aromatic rings, the introduction of complex ring systems, and the degree of the saturation of the molecule as well as the number and ratios of different heteroatoms. As drug molecules derive from both natural and synthetic sources, they cover a joint area in property space of natural and combinatorial compounds. A PCA-based scheme is presented that differentiates the three classes of compounds. It is suggested that by mimicking certain distribution properties of natural compounds, combinatorial products might be made that are substantially more diverse and have greater biological relevance.

Antibiotic drug discovery

“…However, now, after more than two decades of combinatorial chemistry, it became apparent that despite the increased number of new chemical substances, no increase in lead structures or drug candidates has been reached (Newman and Cragg, 2007). Instead, the synthetic, combinatorial library compounds seem to cover only a limited and quite uniform chemical space (Rosén et al ., 2009), whereas existing drugs and particularly natural products exhibit much greater chemical diversity (Feher and Schmidt, 2003). …”

Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles

“…Comparative analyses between compounds often involve cheminformatic analysis of compound structures (3)(4)(5) or retrospective analysis of compound performance by mining the literature (6)(7)(8) or historical data (9,10). For example, intermediate molecular complexity has been suggested as theoretically preferable for drug leads (11), and this relationship is supported by evidence mined from historical data (9).…”

Biologia química: uma estratégia moderna para a pesquisa em produtos naturais

“…Neste sentido, os produtos naturais apresentam estruturas privilegiadas do ponto de vista biológico, uma vez que evoluíram em conjunto com as proteínas durante suas biossínteses e também quando apresentavam atividades biológicas. Além disso, os produtos naturais apresentam uma ampla e complexa diversidade química, com propriedades similares aos fármacos em uso 20 . Como as reações na natureza são altamente influenciadas pela função, cada produto natural deve ter um receptor biológico e, portanto, o receptor será potencialmente um alvo para fármacos.…”