A Chemometric Analysis of Deep-Sea Natural Products

Abstract

Deep-sea natural products have been created by unique marine organisms that thrive in a challenging environment of extreme conditions for its inhabitants. In this study, 179 deep-sea natural products isolated from 2009 to 2013 were investigated by analysing their physicochemical properties that are important indicators of the ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) profile of a compound. The study and analysis of these molecular descriptors and characteristics enabled the defining of these compounds in various chemical spaces, particularly as an indication of their drug-likeness and position in chemical space and is the first to be conducted to analyse deep-sea derived natural products. It was found that ~40% of all deep-sea natural products were drug-like and 2/3 were within Known Drug Space (KDS), highlighting the high drug-likeness of a significant proportion of deep-sea natural products, most of which have already been shown to have notable biological activities, that should be further investigated as potential therapeutics. Furthermore, this study was able to reveal the general structural differences between compounds from Animalia, Bacteria and Fungi organisms where it was observed that natural products from members of the Animalia kingdom are structurally more varied than compounds from bacteria and fungi. It was also noted that, in general, fungi-derived compounds occupy a more favourable position in drug-like chemical space and are a rich and promising source of biologically-active natural products for the purposes of drug development and therapeutic application.

Keywords: chemical space; deep-sea; drug-like; known drug space; lead-like; natural products.

Figure 1

Structures of some marine-derived drugs that are or have been approved for clinical use.

Figure 2

Number of natural products isolated from deep-sea marine organisms, by Kingdom.

Figure 3

Number of natural products isolated from the Animalia Kingdom, by Phylum.

Figure 4

Number of natural products isolated from deep-sea marine organisms of the Porifera Phylum in the Animal Kingdom, by order.

Figure 5

Number of natural products isolated from deep-sea marine bacteria, by Phylum.

Figure 6

The statistical distribution of the molecular weight of all analysed compounds (green = 300 g mol⁻¹, compounds <300 g mol⁻¹ are in the lead-like space; yellow = 500 g mol⁻¹, compounds <500 g mol⁻¹ are in the drug-like space; red= 800 g mol⁻¹, compounds <800 g mol⁻¹are in the KDS. Total number of compounds = 179.

Figure 7

The statistical distribution of the octanol—water partition coefficient (LogP) of all analysed compounds (green = 3, compounds < 3 are in the lead-like space; yellow = 5, compounds < 5 are in the drug-like space; red = 6.5, compounds < 6.5 are in the KDS. Total number of compounds = 179.

Figure 8

The statistical distribution of the hydrogen bond donors of all analysed compounds (green = 3, compounds < 3 are in the lead-like space; yellow = 5, compounds < 5 are in the drug-like space; red = 7, compounds < 7 are in the KDS. Total number of compounds = 179.

Figure 9

The statistical distribution of the hydrogen bond acceptors of all analysed compounds (green = 3, compounds < 3 are in the lead-like space; yellow = 5, compounds < 5 are in the drug-like space; red = 15, compounds < 15 are in the KDS. Total number of compounds = 179.

Figure 10

The statistical distribution of the polar surface area (PSA) of all analysed compounds (green = 60, compounds < 60 Ų are in the lead-like space; yellow = 140, compounds < 140 Ų are in the drug-like space; red = 180, compounds < 180 Ų are in the KDS. Total number of compounds = 179.

Figure 11

The statistical distribution of the rotatable bonds of all analysed compounds (green = 3, compounds < 3 are in the lead-like space; yellow = 10, compounds < 10 are in the drug-like space; red = 17, compounds < 17 are in the known drug space. Total number of compounds = 179.

Figure 12

The statistical distribution of the LogS of all analysed compounds. Total number of compounds = 179.

Figure 13

The statistical distribution of the polarisability of all analysed compounds. Total number of compounds = 179.

Figure 14

Biplot representing the PCA analysis on the studied compounds and molecular descriptors. The arrows represent molecular descriptors and the direction in which they hold influence. Each point represents a molecule in this study (red = animalia, green = bacteria, blue = fungi).

Figure 15

Representation of the contributors to the first principal component. The red reference line corresponds to the expected contribution value for each dimension if the contribution were uniform.

Figure 16

Biplot representing the PCA analysis on the studied compounds and molecular descriptors. The arrows represent molecular descriptors and the direction in which they hold influence. Each point represents a molecule in this study (red = animalia, green = bacteria, blue = fungi).

Figure 17

Correlation matrix to represent the relationships between the molecular descriptors.

Figure 18

Biplot representing the PCA analysis on the compounds isolated from organisms in the Animalia Kingdom and their molecular descriptors (PC1 vs. PC2). The arrows represent molecular descriptors and the direction in which they hold influence. Each point represents a molecule.

Figure 19

Biplot representing the PCA analysis on the compounds isolated from organisms in the Animalia Kingdom and their molecular descriptors (PC2 vs. PC3). The arrows represent molecular descriptors and the direction in which they hold influence. Each point represents a molecule.

Figure 20

Structure of citharoxazole, a lead-like compound isolated from the deep-sea Mediterranean sponge, Latrunculia (Biannulata) citharistae [45].

Figure 21

Drug-like compounds isolated from deep-sea Animalia organisms.

Figure 22

Drug-like compounds isolated from deep-sea Bacteria.

Figure 23

Biplot representing the PCA analysis on the compounds isolated from organisms in the Bacteria Kingdom and their molecular descriptors (PC1 vs. PC2). The arrows represent molecular descriptors and the direction in which they hold influence. Each point represents a molecule.

Figure 24

Biplot representing the PCA analysis on the compounds isolated from organisms in the Bacteria Kingdom and their molecular descriptors (PC2 vs. PC3). The arrows represent molecular descriptors and the direction in which they hold influence. Each point represents a molecule.

Figure 25

Drug-like compounds isolated from deep-sea Fungi.