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 and 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.

Keywords: Cheminformatics; Natural products; Physicochemical properties; Principal component analysis; Synthetic drugs.

Figure 1. Approved drugs 1981–2010

NCEs from 1981–2010 are binned in five-year groups and displayed in three series: total approved drugs (●), small molecules (■), and biologics (▲).

Figure 2. Small-molecule drug approvals between 1981–2010 parsed by compound class

NCEs are binned in five-year periods and displayed as percentages of total small-molecule drug approvals in each time interval. (a) NCEs parsed as drugs based on natural product structures (i.e.: natural products (NP), natural product-derived (ND), natural product-inspired synthetics (S*, S*/NM)) versus drugs from completely synthetic origins (S, S/NM). (b) Drugs based on natural product structures parsed by individual compound classes.

Figure 3. PCA plots of drugs approved between 1981–2010 parsed by compound class

Data from a single analysis are shown on four separate PCA plots defined by the first two principal components, PC1 vs PC2, for (a) natural product drugs (NP), (b) natural product-derived drugs (ND), (c) natural product-inspired synthetic drugs (S*, S*/NM), and (d) completely synthetic drugs (S, S/NM).

Figure 4. Component loadings for the PCA

Vectors on the loading plot indicate the relative influence of each structural and physiochemical descriptor on the placement of molecules on the plot of PC1 vs PC2.