Modelling bioactivities of combinations of whole extracts of edibles with a simplified theoretical framework reveals the statistical role of molecular diversity and system complexity in their mode of action and their nearly certain safety.

Pascal Mayer

doi:10.1371/journal.pone.0239841

Abstract

Network pharmacology and polypharmacology are emerging as novel drug discovery paradigms. The many discovery, safety and regulatory issues they raise may become tractable with polypharmacological combinations of natural compounds found in whole extracts of edible and mixes thereof. The primary goal of this work is to get general insights underlying the innocuity and the emergence of beneficial and toxic activities of combinations of many compounds in general and of edibles in particular. A simplified model of compounds' interactions with an organism and of their desired and undesired effects is constructed by considering the departure from equilibrium of interconnected biological features. This model allows to compute the scaling of the probability of significant effects relative to nutritional diversity, organism complexity and synergy resulting from mixing compounds and edibles. It allows also to characterize massive indirect perturbation mode of action drugs as a potential novel multi-compound-multi-target pharmaceutical class, coined Ediceuticals when based on edibles. Their mode of action may readily target differentially organisms' system robustness as such based on differential complexity for discovering nearly certainly safe novel antimicrobials, antiviral and anti-cancer treatments. This very general model provides also a theoretical framework to several pharmaceutical and nutritional observations. In particular, it characterizes two classes of undesirable effects of drugs, and may question the interpretation of undesirable effects in healthy subjects. It also formalizes nutritional diversity as such as a novel statistical supra-chemical parameter that may contribute to guide nutritional health intervention. Finally, it is to be noted that a similar formalism may be further applicable to model whole ecosystems in general.

Highlights

Network pharmacology and polypharmacology are emerging as novel drug discovery paradigms [1,2,3,4]
The same applies when increased diversity leads to synergy for a desirable activity, and when the complexity of the organisms augments due to the nutritional regimen, for instance through an impact on microbiota diversity. The analysis of this model has been restricted to a linear approximation of the deviation from an average equilibrium value coined the homeostatic value. This precludes the description of the non-linear effects likely found in large deviation from homeostasis, notably the likely emergence of out-of-homeostasis equilibrium states
Decomposing a single feature into two features, a first for the above-homeostasis values and a second for the below-homeostasis values allows to formally use linear models to account for quadratic and asymmetrical effects induced on a dependent feature

Summary

Introduction

Network pharmacology and polypharmacology are emerging as novel drug discovery paradigms [1,2,3,4] They hold promises for overcoming safety and efficacy pitfalls of single compound based therapeutic intervention [5,6,7]. A polypharmacological alternative to combinations of drugs and/or purified natural compounds may be found in the use of (extracts of) whole edibles and mixes thereof, which form readily available complex mixes of natural compounds [10] Their potential use in the rapid development as botanical drugs is facing regulatory challenges because their safety is questioned and their mode of action is considered as unknown [11]. Stated in a more general fashion, chemical compounds may induce desired and undesired effects

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Conclusion