Characterization of the Chemical Space of Known and Readily Obtainable Natural Products

Abstract

Natural products remain one of the most productive sources of chemical inspiration for the development of new drugs. The structures of more than 250 000 natural products are available from public databases. At least 10% of these compounds are readily obtainable for experimental testing from commercial vendors and public research institutions. While the physicochemical properties of known natural products have been thoroughly studied and compared to those of drugs and other types of small molecules, the information available on the content, coverage, and relevance of individual virtual and physical natural product libraries is clearly limited. The aim of this study was the development of a detailed understanding of the coverage of chemical space by known and readily obtainable natural products and by individual natural product databases. For this purpose, we compiled comprehensive data sets of known and readily obtainable natural products from 18 virtual databases (including the Dictionary of Natural Products), nine physical libraries, and the Protein Data Bank (PDB). We also developed and employed an algorithm ("SugarBuster") for the removal of sugars and sugar-like moieties, which are generally not in the focus of interest for drug discovery, from natural products. In addition, we devised a rule-based approach for the automated classification of natural products into natural product classes (alkaloids, steroids, flavonoids, etc.). Among the most important results of this study is the finding that the readily obtainable natural products are highly diverse and populate regions of chemical space that are of high relevance to drug discovery. In some cases, substantial differences in the coverage of natural product classes and chemical space by the individual databases are observed. More than 2000 natural products are identified for which at least one X-ray crystal structure of the compound in complex with a biomacromolecule is available from the PDB.

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

“…[127][128][129] Meanwhile, the accessibility of this chemicals pace for screening campaigns is low: only about 10 %o ft hese compounds are readily available from commercial vendors and public research institutions. [130] Therefore, the isolation of naturale xtracts,t heir screening, and further identification of active components still remain important strategies of drug discovery. [131] Analysis of new drugs entering the market, according to their registration year (1981-2010) and origin (i.e.,s ynthetic, natural, or modified NP), showed that the number of drugs comingf rom natural sources decreased, to al esser extent, over thesey ears comparedw ith fully synthetic compounds ( Figure 27).…”

<strong></strong>LANaPD: Towards a Unified Latin America Natural Products Database

“…One of such key contributions has been the organization and analysis of chemical information of NPs, with or without biological activity, in compound databases. Over the past five years, several reviews of NP databases have been published [17][18][19][20][21]. Some of these reviews include chemoinformatic analysis of the contents, diversity, and coverage of the compounds in chemical space.…”

Functional group and diversity analysis of BIOFACQUIM: A Mexican natural product database

“…As part of these synergistic efforts, curated databases of natural products have an important role as they are major tools for data mining, hypothesis generation, and starting points of virtual screening. There are several databases of natural products in the public domain as reviewed recently 3 . Our research group has reported initial efforts to assemble a database of natural products from Mexico called BIOFACQUIM 4 .…”