Scaffold Diversity of Fungal Metabolites

Abstract

Many drug discovery projects rely on commercial compounds to discover active leads. However, current commercial libraries, with mostly synthetic compounds, access a small fraction of the possible chemical diversity. Natural products, in contrast, possess a vast structural diversity and have proven to be an outstanding source of new drugs. Several chemoinformatic analyses of natural products have demonstrated their diversity and structural complexity. However, to our knowledge, the scaffold content and structural diversity of fungal secondary metabolites have never been studied. Herein, the scaffold diversity of 223 fungal metabolites was measured and compared to the diversity of approved drugs and commercial libraries for HTS containing natural, synthetic, and semi-synthetic compounds. In addition, the global diversity of the fungal isolates was assessed and compared to other reference data sets using Consensus Diversity Plots, a chemoinformatic tool recently developed. It was concluded that fungal secondary metabolites are cyclic systems with few ramifications and more diverse than the commercial libraries with natural products and semi-synthetic compounds. The fungal metabolites data set was one of the most structurally diverse, containing a large proportion of different and unique scaffolds not found in the other compound data sets including ChEMBL. Therefore, fungal metabolites offer a rich source of molecules suited for identifying diverse candidates for drug discovery.

Analysis of a large food chemical database: chemical space, diversity, and complexity

“…The benzene ring is the most common core scaffold in chemical databases used in drug discovery ( Bemis & Murcko, 1996 ; Singh et al ., 2009 ; Yongye et al ., 2012 ). Many of the most frequent scaffolds in FooDB are also common in other compound databases of natural products ( González-Medina et al ., 2017 ). In a follow-up work, it will be interesting to explore the type of functional groups commonly present in the acyclic structures of FooDB.…”

“…Despite the high relevance of food chemicals in many areas including nutrition, disease prevention, and broad impact in the food industry, the chemical space and diversity of food chemical databases ( Minkiewicz et al ., 2016 ) has been quantified on a limited basis. Previous efforts include the analysis and comparison of about 2,200 Generally Recognized as Safe (GRAS) flavoring substances (discrete chemical entities only) with compound databases relevant in drug discovery and natural product research e.g., drugs approved for clinical use, compounds in the ZINC database, and natural products from different sources ( Burdock & Carabin, 2004 ; González-Medina et al ., 2016 ; González-Medina et al ., 2017 ; Martinez-Mayorga et al ., 2013 ; Medina-Franco et al ., 2012 ; Peña-Castillo et al ., 2018 ). Other food-related chemical databases, comprising around 900 compounds, were analyzed by Ruddigkeit and J.-L. Reymond ( Ruddigkeit & Reymond, 2014 ).…”

Media studies to enhance the production of verticillins facilitated by in situ chemical analysis

“…Fungi are a rich resource for biologically active and structurally diverse secondary metabolites [ 16 , 26 , 27 ]. As such, a number of authors have noted the value of investing in fungi as a source of new drug leads, especially to treat cancer and overcome its resistance [ 6 , 44 ].…”

Cheminformatics in Natural Product‐based Drug Discovery

“…The third property of choice is represented by color coding of the data points, and the fourth one (intuitively, this would be the database size) is represented by the size of the data point. The method has been used for the visual comparison of multiple smallmolecule databases [83,[94][95][96] and is accessible via a web service. [93] Recently, researchers from the same group reported the development of a new method for the representation of the chemical space of compound databases by a single fingerprint called Statistical-Based Database Fingerprint (SB-DFP).…”