Chemoinformatic Expedition of the Chemical Space of Fungal Products

Abstract

Aim: Fungi are valuable resources for bioactive secondary metabolites. However, the chemical space of fungal secondary metabolites has been studied only on a limited basis. Herein, we report a comprehensive chemoinformatic analysis of a unique set of 207 fungal metabolites isolated and characterized in a USA National Cancer Institute funded drug discovery project. Results: Comparison of the molecular complexity of the 207 fungal metabolites with approved anticancer and nonanticancer drugs, compounds in clinical studies, general screening compounds and molecules Generally Recognized as Safe revealed that fungal metabolites have high degree of complexity. Molecular fingerprints showed that fungal metabolites are as structurally diverse as other natural products and have, in general, drug-like physicochemical properties. Conclusion: Fungal products represent promising candidates to expand the medicinally relevant chemical space. This work is a significant expansion of an analysis reported years ago for a smaller set of compounds (less than half of the ones included in the present work) from filamentous fungi using different structural properties.

Consensus Diversity Plots: a global diversity analysis of chemical libraries

“…3 emphasize that approved anticancer and non-anticancer drugs have different profiles of diversity, including physicochemical properties. Putting together these observations with previous analyses comparing approved anticancer and non-anticancer drugs [34] confirm that concepts such as “drug-likeness” highly depend on the type of drugs being analyzed.…”

“…In MOE, the six properties have the following notation: a_don, a_acc, SlogP, Weight, TPSA, and b_rotN, respectively. These molecular descriptors have been used to measure the diversity of compound databases [34–36]. The distance (or dissimilarity ) between any two data sets, D u and D v , was computed using the Euclidean distance function [31] as follows.…”

Scaffold Diversity of Fungal Metabolites

“…The chemotype diversity was analyzed for a unique in-house library of 223 fungal metabolites (El-Elimat et al, 2012; Gonzalez-Medina et al, 2016). For reference, five data sets containing between 76 and 2,500 compounds were included in the analysis: compounds based on the FEMA GRAS list (hereafter referred to as GRAS; Burdock et al, 2006; Medina-Franco et al, 2012); FDA approved drugs obtained from DrugBank, version 4.0 (Wishart et al, 2006; Law et al, 2014) subdivided into: anticancer and non-anticancer drugs; and two datasets from a commercial vendor (http://www.ac-discovery.com) containing mostly natural products derived from plants (MEGx) and semi-synthetic compounds (NATx).…”

“…To compare the data sets, six properties of pharmaceutical relevance were calculated with MOE software: hydrogen bond donors (HBD), hydrogen bond acceptors (HBA), the octanol/water partition coefficient (LogP), molecular weight (MW), topological polar surface area (TPSA), and number of rotatable bonds (RTB). These molecular descriptors have been used previously to measure molecular properties diversity (Gonzalez-Medina et al, 2016). …”

“…In that work it was concluded that fungal metabolites had a high overlap with the chemical space of anticancer drugs, which was an encouraging finding for the ongoing efforts to discover active anticancer compounds of fungal origin (Kinghorn et al, 2016). Gonzalez-Medina et al (2016) analyzed a larger data set with 207 fungal isolates, adding more information on structural complexity and diversity of the fungal metabolites. In that work fungal metabolites were demonstrated to be more complex than approved drugs and commercial libraries, and as complex as compounds used in the food industry, Generally Recognized as Safe (GRAS).…”