Cheminformatic comparison of approved drugs from natural product versus synthetic origins

Abstract

Despite the recent decline of natural product discovery programs in the pharmaceutical industry, approximately half of all new drug approvals still trace their structural origins to a natural product. Herein, we use principal component analysis to compare the structural and physicochemical features of drugs from natural product-based versus completely synthetic origins that were approved between 1981–2010. Drugs based on natural product structures display greater chemical diversity and occupy larger regions of chemical space than drugs from completely synthetic origins. Notably, synthetic drugs based on natural product pharmacophores also exhibit lower hydrophobicity and greater stereochemical content than drugs from completely synthetic origins. These results illustrate that structural features found in natural products can be successfully incorporated into synthetic drugs, thereby increasing the chemical diversity available for small-molecule drug discovery.

Chemoinformatic Expedition of the Chemical Space of Fungal Products

“…Three measures were used to compare the structural complexity of the datasets: fraction of sp 3 carbon atoms (F-sp 3 ), fraction of chiral centers (CCF) and globularity (GLOB). F-sp 3 and CCF are complexity metrics that have been used broadly to measure MC [34,35].…”

“…F-sp 3 and CCF are complexity metrics that have been used broadly to measure MC [34,35]. A higher value of CCF means higher stereochemical complexity and a larger F-sp 3 value indicates that the molecule is more likely to have a 3D structure, in other words, a nonplanar structure.…”

“…3D structures are preferred over planar structures with the hypothesis that molecules with outof-plane substituents could adjust their molecular shape and increase receptor/ligand complementarity [34]. However, only considering sp 3 carbons may not be enough to determine if a molecule has a 3D structure: F-sp 3 does not account for 3D structures given by sp 3 -hybridized heteroatoms. However, GLOB does capture this structural feature.…”

“…GLOB evaluates the resemblance of a compound to a sphere, a value equal to 1 represents a spherical molecule while a value equal to 0 represents a structure that is completely flat. F-sp 3 was computed with Maya ChemTools [36], dividing the number of sp 3 hybridized carbons by the total carbon count; CCF was calculated using Molecular Operating Environment software dividing the number of chiral centers (ChC) by the total carbon count. GLOB was calculated with Molecular Operating Environment software using the conformation with a low-energy conformation.…”

“…From such studies it has been concluded that, in general, natural products have larger size, greater 3D complexity, lower hydrophobicity, increased polarity and fewer aromatic rings than other compound libraries [3].…”