Novel chemical space exploration via natural products

Abstract

Natural products (NPs) are a rich source of novel compound classes and new drugs. In the present study we have used the chemical space navigation tool ChemGPS-NP to evaluate the chemical space occupancy by NPs and bioactive medicinal chemistry compounds from the database WOMBAT. The two sets differ notably in coverage of chemical space, and tangible leadlike NPs were found to cover regions of chemical space that lack representation in WOMBAT. Property based similarity calculations were performed to identify NP neighbors of approved drugs. Several of the NPs revealed by this method were confirmed to exhibit the same activity as their drug neighbors. The identification of leads from a NP starting point may prove a useful strategy for drug discovery in the search for novel leads with unique properties.

Figure 1

Predicted score (tPS) plots illustrating the difference in coverage of biologically relevant chemical space by natural products (NPs, in green) and bioactive medicinal chemistry compounds from the database WOMBAT (in black) in the first three principal components. NPs cover parts of chemical space that lack representation in medicinal chemistry compounds, indicating that these areas have yet to be investigated in drug discovery. They appear to contain lead-like NPs that could subsequently be of interest in drug discovery.

Figure 2

An overview of the analyzed low density regions (NPs in green, medicinally chemistry compounds in black). Briefly, the first four dimensions of ChemGPS-NP can be interpreted as follows; size increases in the positive direction of PC1; compounds are increasingly aromatic in the positive direction of PC2; lipophilic compounds are situated in the positive direction of PC3 and polar in the negative direction; compounds are increasingly flexible in the positive direction of PC4 and more rigid in the negative direction. Regions I and II enclose smaller compounds than average. Region III holds compounds with increased aromaticity. In regions IV, V and VI reside compounds with increasing size in positive direction of PC1, and less aromatic features in negative direction of PC2. Region VII contains rather flexible, average sized compounds, while region VIII encloses fairly rigid, average sized compounds. Compounds in region IX are increasingly rigid and large. Region X contains compounds that are generally larger than average, and increasingly flexible in the positive direction of PC4.

Figure 3

Distribution of ED to the nearest NP neighbour for the drugs in GVKBIO_DD. The cumulative number of drugs is plotted against the ED to the closest NP neighbour.

Figure 4

Chemical structures of drugs with shared mode of action used to calculate within group EDs; the angiotensin-converting enzyme (ACE) inhibitors enalapril (1a) and lisinopril (1b), the angiotensin receptor 1 (AT1) antagonists losartan (2a) and valsartan (2b), the calcium channel (CaCh) blockers amlodipine (3a) and felodipine (3b), the β1–adrenergic receptor (β1) blockers metoprolol (4a) and atenolol (4b), the proton pump inhibitors (PPIs) lansoprazole (5a) and omeprazole (5b), the histamine 2 (H2) receptor antagonists ranitidine (6a) and famotidine (6b), the H1 receptor antagonists cetirizine (7a) and loratidine (7b), the monoamine oxidase (MAO) inhibitors moclobemide (8a) and selegeline (8b), the selective serotonin re-uptake inhibitors (SSRIs) citalopram (9a) and fluoxetine (9b), the HIV-1 protease (PR) inhibitors indinavir (10a) and ritonavir (10b), the HIV-1 integrase (IN) inhibitors raltegravir (11a) and elvitegravir (11b), and the HIV-1 reverse transcriptase (RT) enzyme inhibitors zidovudine (12a), and lamivudine (12b). EDs are given in parentheses.

Figure 5

Chemical structures of drug/NP pairs. The ED between the compounds is given in parentheses under the corresponding drug/NP pair. The proportion of NPs in DNP with similar or shorter EDs than the selected examples is given in parentheses, in percent, after each NP example, where 0% means that this was the single closest NP. (A) The aromatase inhibitor formestane (13a) and its NP neighbours 13b–d (0, 0.6, and 0.4% respectively). (B) The anticoagulant drug warfarin (14b) and its NP neighbours 14a (0%), 14c (0%), and 14d (0%). (C) The antidepressant drug moclobemide (8a) with NP neighbour 15 (6.4%). (D) The HIV-1 RT inhibiting drugs lamivudine (12b) and zalcitabine (16b) and their NP neighbours 16a (14%), 16c–e (0%). (E) The investigational new HIV-1 IN inhibiting drug (in phase III clinical trials) (11b) with NP neighbour 17 (8.4%). (F) The antihypertensive drug amlodipine (3a) and it NP neighbour 18 (7.3%). (G) The antiviral drug zanamivir (19a) with close NP neighbours 19b (0.05%), from which zanamivir was derived, and 19c (0%). (H) The antilipemic drug simvastatin (20a) and its close NP neighbours 20b (0.03%), from which simvastatin was originally derived, 20c (0.01%), and 20d (0.01%).