DOI: 10.1002/minf.
201000163
Back to the Roots: Prediction of Biologically Active Natural
Products from Ayurveda Traditional Medicine
Honey Polur,[a] Tejal Joshi,[a] Christopher T. Workman,[a] Gandhidas Lavekar,[b] and Irene Kouskoumvekaki*[a]
Presented at the 18th European Symposium on Quantitative Structure Activity Relationships, EuroQSAR 2010, Rhodes, Greece
Abstract: Ayurveda, the traditional Indian medicine is one
of the most ancient, yet living medicinal traditions. In the
present work, we developed an in silico library of natural
products from Ayurveda medicine, coupled with structural
information, plant origin and traditional therapeutic use.
Following this, we compared their structures with those of
drugs from DrugBank and we constructed a structural simi-
larity network. Information on the traditional therapeutic
use of the plants was integrated in the network in order to
provide further evidence for the predicted biologically
active natural compounds. We hereby present a number of
Keywords: Natural products Ayurveda Structural similarity Traditional medicine Biological activity
1 Introduction
Traditional medicines are used by 60 % of the worlds popu-
lation. The World Health Organization (WHO) lists 21 000
plants used for medicinal purposes all over the world.
Among these, 2500 species are in India and 150 of them
are used commercially on a reasonably large scale, making
India the largest producer of medicinal herbs in the
world.[1]
Traditional medicines have been identified through real
life experiences and direct observations in people with dis-
eases and represent highly complex biological systems. Tra-
ditional Indian Medicine (TIM), also known as Ayurveda, in
particular, was originated and developed between 2500
and 500 BC and has accumulated many generations of ob-
servations with well-organized and documented data.[2] It
could, thus, be regarded as an informative repository of
clinically proven natural products (NPs) that work effec-
tively and safely.[3]
It has long been recognized that NP structures have the
characteristics of high-chemical diversity, biochemical spe-
cificity and other molecular properties that make them fa-
vorable as lead structures for drug discovery. But even
though it is generally accepted that they contain inherently
large-scale structural diversity and could play a protagonist
role for discovering new drugs, assessing this diverse chem-
ical space efficiently and effectively has remained a chal-
lenge for medicinal chemists and pharmacologists. Collec-
tion and isolation of all the available NPs, followed by
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examples where the traditional medicinal use of the plant
matches with the medicinal use of the drug that is structur-
ally similar to a plant component. With this approach, we
have brought to light a number of obscure compounds of
natural origin (e.g. kanugin, norruffscine, isoazadirolide)
that could provide the basis and inspiration for further lead
development. Apart from the identification of novel natural
leads in drug discovery, we envisage that this integrated in
silico ethnopharmacology approach could find applications
in the elucidation of the molecular basis of Ayurveda medi-
cine and in drug repurposing.
random screening for every target is impractical, both eco-
nomically and with respect to time.
It is, therefore, not surprising that the chemoinformatics
community has recently set focus on the application of
computational approaches for the identification of bioac-
tive NPs, which is further demonstrated by the amount of
recent review articles in the field.[47]
Nevertheless, actual in silico research involving NPs is still
rather rare in the scientific literature. Recent studies focus
either on the exploration of the chemical space covered by
NPs,[810] or on the application of NP libraries in ligand-
based[1114] and target-based[15, 16] virtual screening.
In Traditional Chinese Medicine (TCM) research in particu-
lar, a number of studies have recently emerged, which
apply data-mining[17, 18] and systems biology approaches[19]
to explore the molecular basis of TCM and to relate its ter-
minology with the western medicinal context.
A distinct bottleneck in the in silico evaluation of the bio-
logical activity of NPs has been the unavailability of large
[a] H. Polur, T. Joshi, C. T. Workman, I. Kouskoumvekaki
Department of Systems Biology, Center for Biological Sequence
Analysis, Technical University of Denmark
Kemitorvet, Building 208, DK-2800 Lyngby, Denmark
phone/fax: + 45 45256162/ + 45 45931585
*e-mail: irene@cbs.dtu.dk
[b] G. Lavekar
Senior Consultant (Tech.) National Medicinal Plants Board,
Chandralok Building, 36-Janpath, New Delhi-110001, India
181
Full Paper
NP databases with structural and biological information, es-
sential in order to make NPs accessible for virtual screening.
Only few, commercially available databases exist, the most
comprehensive being the Dictionary of Natural Product Da-
tabase (Chapman and Hall), a structure database containing
over 226,000 NPs, with no information, however, about
their biological target. A number of proprietary databases
also exist, such as the Chinese Natural Product Database
developed at the Shanghai Institute of Materia Medica,
which are focused on TCM and contain structural informa-
tion of plant components and TCM usage described ac-
cording to TCM principles.
The current state of NP databases manifests that the
knowledge on traditional medicinal usage has not been
fully exploited as yet. In addition to this, it is apparent that
visibility of Ayurvedic medicine remains much lower as
compared with TCM.[2]
In the present study, we developed an in silico library of
NPs from Ayurveda medicine, coupled with structural infor-
mation, plant origin and traditional therapeutic use. Subse-
quently, we made use of the traditional therapeutic indica-
tion of the plants according to Ayurveda, to support pre-
dicted biological activities of the NPs they consist of, which
were based on structural similarity pairings with drug com-
pounds. We envisage that this integrated in silico ethno-
pharmacology approach could be of use in the elucidation
of the molecular basis of the therapeutic activity of Ayurve-
da medicinal plants, drug repurposing, as well as the iden-
tification of novel chemical entities with attractive scaffolds
for drug discovery.
2 Methods and Material
2.1 Data Sets
The chemical space of Ayurveda NPs with known biological
activity was captured by mapping the compounds against
ChemProt.[20] ChemProt is a repository of 700,000 unique
chemicals with biological activity for more than 30,500 pro-
teins, assembled from both proprietary and freely available
databases, including ChEMBL (version chembl 05),[21] Bind-
ingDB,[22] PDSP Ki Database,[23] DrugBank (version 2.5),[24]
PharmGKB,[25] WOMBAT (version 2009), WOMBAT-PK (version
2008),[26] PubChem bioassay (2010),[27] CTD (version 2009)[28]
and STITCH (version STITCH 2.0).[29]
The data set of small molecule drugs was downloaded
from the DrugBank v. 2.5[24] and consisted of 4887 com-
pounds, referred to in DrugBank as small molecule struc-
tures. All compounds were extracted in SDF format and
were imported in Molecular Operating Environment (MOE,
v.2008.10).[30] All structures were washed, i.e. all ionizable
groups were coordinated with neutral pH conditions, and
energy minimized using the MMFF946 force field.
The original Ayurveda data set was provided in a flat file
format by the Central Council for Research in Ayurveda and
Sidha, Department of AYUSH, Indian Ministry of Health and
182 www.molinf.com  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
H. Polur et al.
Family Welfare. It included 300 plant species with informa-
tion on botanical name, part used, Sanskrit name, chemical
constituents and traditional medical usage.
As the original data set did not contain structural infor-
mation, it was first processed with Reflect.[31] Reflect is a
consolidated dictionary that links names and synonyms to
source data entries and currently contains 4.3 million small
molecules. 1482 compound names from the original Ayur-
veda data set were annotated with a CID (Compound ID)
from Reflect and a final list of 1184 compounds with
unique CIDs was obtained after removing the duplicates.
The list of CIDs was subsequently used to query PubChem
and all structures were retrieved in a single SDF. The chemi-
cal structures corresponding to 645 chemical names that
had not been tagged by Reflect were manually retrieved
from the literature and added to the SDF. The final data set
consisted of 1829 unique NPs from 295 Ayurveda plants
and was imported in MOE. All structures were washed and
energy minimized as before, using the MMFF946 force
field.
2.2 Molecular Descriptors and Similarity Evaluation
Five descriptors related to drug-likeness were calculated in
MOE, namely molecular weight (MW), hydrogen bond
donors (HB-donors), hydrogen bond acceptors (HB-acc),
number of rings and number of rotatable bonds.
According to the Similarity Principle, compounds with
similar chemical structures usually possess similar physico-
chemical properties and biological activities.[32] This is the
underlying assumption for making predictions for new
compounds with biological activity. The chemical structures
were encoded using two types of fingerprints that capture
different levels of similarities between molecules. The 166
keys MACCS fingerprints encode the presence or absence
of predefined substructural or functional groups.[33] The
Gpi-DAPH3 pharmacophore fingerprints are based on an
expansion of the PATTY pharmacophore feature recognition
scheme.[34] This scheme assigns one or more pharmaco-
phore feature types to all the atoms in a molecule based
on a predefined list of SMARTS queries. The pharmaco-
phore feature types are: hydrogen-bond donor (D), hydro-
gen-bond acceptor (A), polar = donor & acceptor (P) and
hydrophobic (H). In addition, an extra label (p or pi) can be
added to each feature if the originating atom or group is
sp2-hybridized or planar for other reasons. Gpi-DAPH3 is
expressed as triplet feature combinations with a graph
based inter-atom distance binning scheme. Both types of
fingerprints are implemented in MOE.
The similarity between two molecules was measured
using the Tanimoto coefficient (Tc).[35] Tc is calculated from
the number of bits in common divided by the total
number of bits in both molecules and ranges between zero
(maximum dissimilarity) and one (maximum similarity). In
the case of MACCS fingerprints we used a cutoff of 0.85 as
the empirical threshold for correlating structural similarity
Mol. Inf. 2011, 30, 181 187
Biologically Active Natural Products fromAyurveda Traditional Medicine

with biological activity.[36] As Gpi-DAPH3 pharmacophore

fingerprints are stricter, geometry-based similarity descrip-
tors, a lower cut-off of 0.50 was used.

2.3 NPDrug Network

The similarity-based network connecting NPs with drugs
was constructed in Cytoscape v. 2.6.3. A NP node and a
drug node were linked when their structural similarity ex-
ceeded the corresponding threshold.

3 Results and Discussion

3.1 Overview of TIM Database
The final TIM database consists of 1829 unique NPs from
295 Ayurveda plants. Most compounds are selectively
found in a few plants. As many as 1308 compounds are
specific to only one plant, while, only 29 compounds are
encountered in more than 10 plants each (see Figure 1). All
NPs listed in Figure 1 are well-studied compounds, with
CIDs that Reflect was able to extract from the public
domain and biological activities that have been already elu-
cidated and documented in the scientific literature.
Beta sitosterol, a phytosterol, is the most common of the
studied NPs, found in 91 of the 295 TIM plants. Other
common compounds belong to the groups of fatty acids,
terpenes, phytosterols and polyphenols and, jointly, they
are components of a total of 182 plants out of 295, which
corresponds to 62 % of the plants in TIM.
In order to assess the chemical diversity spanned by NPs
and to compare it to the diversity of known drugs, we cal-
culated five properties of small molecules relevant to drug-
likeness. These properties include molecular weight,
number of rings, number of rotatable bonds and number
of hydrogen bond acceptors and donors. The mean and
standard deviation values are summarized in Table 1. It can
be deduced from the values shown in the table that NPs
are slightly more complex molecules on average, have a
higher number of rings and less rotatable bonds. Further-
more, while hydrogen bond donors have similar distribu-
tion for both databases, NPs have, on average, more hydro-
gen-bond acceptors and a higher variability. However, the
Figure 1. 29 compounds from TIM database that are present in
more than 10 plants each. Terpenes, phytosterols, fatty acids and
polyphenols indicated by bar shade.
overall differences between the two datasets are smaller
than seen in earlier studies using different compound data-
bases.[6] This observation could hint to the fact that the em-
pirical selection and use of Ayurveda medicinal plants has
led to a group of plants whose constituents are more drug-
like than a random set of NPs.
3.2 Biologically Active Chemical Space of TIM
Mapping the 1829 compounds from TIM database against
ChemProt captured all NPs with known biological activities.
In total, 555 NPs are present in ChemProt with annotated
activities against one or more biological targets. They rep-
resent 30 % of the entire TIM database and they cover 288
of the plants. This analysis indicates that there is still a lot
of hidden potential in TIM, which we believe can be unrav-
eled with the aid of in silico tools. As shown in Figure 2, fol-
lowing the similarity approach described in the Methods

Table 1. Mean and standard deviation values of selected physicochemical properties related to drug-likeness for NPs from TIM and com-
pounds from DrugBank. The considered properties are: molecular weight (MW), hydrogen bond donors (HB-donors), hydrogen bond ac-
ceptors (HB-acc), number of rings and number of rotatable bonds.
Mean Standard deviation
TIM DrugBank TIM DrugBank
MW 379.5 363.8 257.1 307.5
HB-donors 2.6 2.2 4.3 3.8
HB-acc 4.7 3.8 6.8 5.1
# rings 3.4 2.3 2.4 2.0
# rotatable bonds 4.7 6.7 6.4 9.9

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Full Paper
Figure 2. Number of NPs with predicted biological activity using
MACCS and GpiDAPH3 fingerprints and Tc threshold of 0.85 and
0.5 respectively.
section, we identified 811 NPs from TIM with structural sim-
ilarity higher than 0.85 to at least one drug based on
MACCS fingerprints. When GpiDAPH3 fingerprints were
used, 432 NPs from TIM were found similar to at least one
drug, 85 of them with structures that were not retrieved
using MACCS.
3.3 NPDrug Network
The NPDrug network is constructed by linking a NP node
and a drug node when their structural similarity exceeds
the corresponding threshold. NPs with Tc = 1 with a drug
compound have been removed from the network, as either
their biological targets are already known or they are close
structural analogues of known drug compounds. At the
first stage of the analysis that the present study covers, the
aim is to use the traditional Ayurveda medicinal knowledge
for the identification of novel NPs with biological activities.
Therefore, we focus on those NPs, whose medicinal annota-
tion from DrugBank and traditional use stated in TIM are
overlapping. For this reason, the 29 compounds listed in
Figure 1 that are found in more than 10 plants have also
been excluded from the network, as they are connected to
multiple traditional therapeutic uses. Figure 3 depicts the
constructed NPDrug network, as well as selected NPDrug
pairs, for which the predicted medicinal activity of the NP
is validated by the traditional use of the plant(s) that con-
tain it. The 2D structures of the selected NP-Drug pairs are
listed in Figure 4.
Cissampelospareira, known in Ayurveda as Patha, has
been traditionally used as skeletal muscle relaxant. From
the NP-Drug network we identified four of its major constit-
uents, namely cycleanine, insularine, bebeerine and nor-
ruffscine, as the plants bioactive components. Cycleanine,
insularine and bebeerine are structurally similar to tubocur-
arine, the first neuromuscular blocking agent introduced in
clinical anesthesia practice in 1942.[37] The use of cycleanine
and insularine as skeletal muscle relaxants has already been
reported in the literature.[38] However, as they are not in-
cluded in DrugBank, our prediction was solely based on
their structural information. The bioactive properties of be-
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H. Polur et al.
beerine have not been investigated to our knowledge. Nor-
ruffscine shows high structural similarity to papaverine, an
opium alkaloid used as vasodilator, antispasmodic and
smooth muscle relaxant.[39] We found no scientific reports
of experimental biological activities for this compound, but
the joint evidence from TIM and chemoinformatics point
towards its potential activity as muscle relaxant.
Toddaline and dihydroavicine are components of Todda-
liaasiatica, known in TIM as Katulguma and used as stom-
achic, antipyretic and antidiarrheal. Both compounds are
similar to berberine, a compound used as antidierrhal.
The leaves of the Ayurvedic plant Nimba (Azadirachtaind-
ica) are traditionally used in anti-inflammatory treatment.
Nimba contains isoazadirolide, a NP with very little informa-
tion available in the scientific literature. Isoazadirolide is
linked in the network to two drug compounds, namely des-
onide and fluocinonide. Desonide is a corticosteroid agent
used topically for dermatoses (eczema), while fluocinonide
is a topical glucocortisoid used in the treatment of eczema.
Betulin is a triterpene present in six different plants used
in Ayurveda. We identified it to be structurally similar to
calcidiol, a major circulating metabolite of vitamin D3, pro-
duced in the liver and used in the treatment of rickets (in
children) and osteomalacia (in adults). All six plants contain-
ing betulin are traditionally used against chronic rheuma-
tism, a disease closely related to the above.
Acoruscalmus, known in Ayurveda as Vaca, has been tra-
ditionally used against a wide range of diseases, including
external treatment of skin eruptions. We identified acore-
none, one sesquiterpene plant component, as structurally
similar to camphor, a bicyclicmonoterpeneketone that is
used topically as skin antipruritic.
Kanugin is another NP for which very little information is
available in the scientific public domain. It is a major com-
ponent of the stem bark of Pongamiapinnata, a plant
known is Ayurveda as Karanja that is used in the treat-
ments of vaginopathy, and dermatopathy conditions. Our
approach linked it to podofilox, a natural lignan drug
against genital warts and skin cancers.
Podofilox has been also found structurally similar to one
other NP from TIM, namely clusin, from the plant Piper
cubeba, or Kankola, according to Ayurveda. The oil of Piper
cubeba has been known for its antiviral properties and has
been traditionally used against influenza virus and Bacilus-
typhosus. Although the antiviral properties of podofilox are
not mentioned in DrugBank, they are documented else-
where in the scientific literature.[40]
As a last example, Hydnocarpus laurifolia is a plant found
in Aryuveda medicine under the name of Tuvaraka, whose
seeds are used against skin disorders. It contains aleprestic
acid, a natural compound that has been linked to azelaic
acid. Azelaic acid is an approved drug compound with anti-
microbial properties, effective against a number of skin
conditions, such as acne.
Mol. Inf. 2011, 30, 181 187
Biologically Active Natural Products fromAyurveda Traditional Medicine

Figure 3. NPDrug network generated by using structural similarity information between NPs from Ayurveda medicine (ellipse) and drugs
from DrugBank (diamonds). A link is placed between a NP node and a drug node if the Tanimoto coefficient is higher than 0.85 and 0.50
for MACCS and GpiDAPH3 fingerprints respectively. Examples of NP-Drug sub-networks, where the therapeutic use of the drug matches
with the traditional use of the plant(s) that contain the NP, are magnified.

4 Conclusions lowing the structural similarity principle, we predicted bio-

logical activity for a number of novel natural compounds
Our intention with the present work has been to demon- from Ayurveda medicine. These compounds were found
strate the benefits from integrating traditional medicinal similar mostly to other NPs already accepted for use in
knowledge in chemoinformatics-driven drug discovery. Fol- western medicinal practice. This is not surprising, consider-

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Full Paper H. Polur et al.

Figure 4. 2D structures of the compounds from the magnified sub-networks of Figure 3.

ing that before the advent of high-throughput screening, comparison between NPs from Ayurveda and drugs, we are
more than 80 % of drug substances were NPs or inspired the first to develop a TIM database with structural informa-
by nature and almost half of the drugs approved since tion and of a size that allows its application in virtual
1994 are based on NPs.[7] For the purpose of the structural screening. With this database, we have brought to light a

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Biologically Active Natural Products fromAyurveda Traditional Medicine

number of obscure compounds of natural origin (e.g. kanu- [9] N. Singh, R. Guha, M. A. Giulianotti, C. Pinilla, R. A. Houghten,
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