Scientific African 20 (2023) e01593

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Scientific African
journal homepage: www.elsevier.com/locate/sciaf

Applications of molecular docking in natural products-based

drug discovery
Isaac Asiamah a,∗, Samuel Asiamah Obiri a, Woasiedem Tamekloe b,
Francis Ackah Armah b, Lawrence Sheringham Borquaye c,d
a
Department of Chemistry, School of Physical Sciences College of Agriculture and Natural Sciences, University of Cape Coast, Cape Coast,
Ghana
b
Department of Biomedical Sciences, School of Allied Health Sciences College of Health and Allied Health Sciences, University of Cape
Coast, Cape Coast, Ghana
c
Department of Chemistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
d
Central Laboratory, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

a r t i c l e i n f o a b s t r a c t

Article history: Natural products have a long history of use in the treatment of various diseases particu-
Received 24 September 2022 larly in developing countries. The use of compounds of natural origin as lead compounds
Revised 2 February 2023
for the development of conventional drugs is widely recognised. Natural product-based
Accepted 16 February 2023
drug discovery efforts in developing countries mostly involve the use of crude extracts
in in-vitro and/or in-vivo assays. There are limited efforts at isolating active principles for
Editor: DR B Gyampoh structure elucidation studies. Studies that isolate pure secondary metabolites and charac-
terize their structures have limited bioactivity evaluations. In conventional drug discovery
Keywords:
programs, molecular docking serves as a useful tool for predicting interactions of small
Natural products
molecules with drug target(s) to guide synthesis decisions. Medicinal chemists use this
Drug discovery and development
Molecular docking tool to predict and synthesize compounds likely to have pharmacological activity and thus
Phytochemicals save time and cost for drug discovery. Efforts have been made to incorporate molecular
Ligands docking techniques into natural products-based drug discovery. The objective of this re-
Protein target view is to discuss molecular docking in natural product drug discovery programs with the
goal of providing easy-to-understand information to help beginners interested in incorpo-
rating molecular docking in their research. This is expected to enhance natural product
screening programs by predicting which phytochemicals are likely to show success, es-
pecially in new disease situations such as COVID-19. Applications in the repositioning of
plants for emerging conditions are also discussed.
© 2023 The Authors. Published by Elsevier B.V. on behalf of African Institute of
Mathematical Sciences / Next Einstein Initiative.
This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/)

Introduction

Natural products have a long history of use as sources of medicine. Indeed, compounds derived from natural sources
continue to serve as chemical scaffolds for further development into conventional medicines. The unique chemical diversity

∗
Corresponding author.
E-mail address: iasiamah1@ucc.edu.gh (I. Asiamah).

https://doi.org/10.1016/j.sciaf.2023.e01593
2468-2276/© 2023 The Authors. Published by Elsevier B.V. on behalf of African Institute of Mathematical Sciences / Next Einstein Initiative. This is an
open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
I. Asiamah, S.A. Obiri, W. Tamekloe et al. Scientific African 20 (2023) e01593

Fig. 1. Workflow of natural product-based drug discovery by natural products scientists mostly in developing countries. The process starts with plant
selection, extractions, and bioassays of crude extracts or solvent fractions; pure compound isolation, characterization, and bioassays are limited.

of compounds from natural sources presents the chance to discover chemically novel compounds which will likely escape
the imagination of the most talented synthetic medicinal chemists. Although interest in natural products died down for a
while among pharmaceutical companies, the failed potential promise of combinatorial chemistry has renewed interest in
natural products for lead identification [14,20,45]. The renewed interest is justified given the proven track record of natural
products as lead compounds for almost 50% of approved drugs on the market [20,62,63]. Compounds of natural origin will
continue to show promise as leads because of their unique chemotypes. In developing countries where herbal medicines
receive the most patronage [14], natural product scientists make efforts to find scientific evidence to support the traditional
uses of various medicinal plant species. Typically, crude extracts of plants are tested in in-vitro or in-vivo disease models
for specific disease conditions based on traditional applications [8,25,26,34,43,44]. While these bioactivity tests are useful
first steps, they are far from providing substantiated evidence for claimed traditional uses. In other studies where pure com-
pounds are isolated and characterized, biological activity studies are limited due to insufficient access to compounds. Crude
extracts have multiple components and therefore activity may result from two or more compounds working in synergy. This
is evidenced by cases where crude extracts have demonstrable activity, but pure isolates have little or no biological activity
in the same disease models. Even more concerning is the fact that observed biological activities in these models may not be
applicable to the human situation. In addition to the lack of requisite equipment and access to natural product databases to
support structure elucidation efforts, compound scale-up to allow exhaustive biological studies remain a challenge among
natural product scientists in developing countries.
Despite the inherent shortcomings of molecular docking, the technique continues to be a useful tool in drug discov-
ery programs [10,22,32,51]. Molecular docking of compounds in various databases helps to virtually screen large numbers
of small molecules in an effort to identify potential hits [23]. These predictions save time, and cost as well as introduce
unique molecular scaffolds into the discovery pipeline [51]. The application of molecular docking in natural products-based
drug discovery programs can help to explain some traditional uses and potentially identify new uses for medicinal plants
[23]. Ethnopharmacological knowledge of plant uses precludes new and emerging diseases. Molecular docking of known
phytochemicals on appropriate drug target(s) of new diseases such as COVID-19 provides clues about which plants can be
targeted for biological activity screening [12,42]. Therefore, this review intends to discuss molecular docking approaches in
natural products-based drug discovery programs. It seeks to provide ideas on where to start and what tools are available to
get beginners started. The suggested steps are not exhaustive but are expected to serve as starting points for scientists new
to docking to explore potential applications of computer-aided drug discovery (CADD) approaches in natural products-based
drug discovery research.

Selection of plant

The use of plants in folkloric medicine serves as the major basis for the selection of plants for natural products drug
discovery research. People in developing countries have used herbs in traditional preparations to treat various ailments.
The traditional knowledge is passed down to the next generation, in most cases, without formal documentation. Efforts
have been made in various developing countries to document the traditional uses of plants [3,5,8,11,53,57]. In Ghana, for
example, the pharmacopeia of medicinal plants has been published [13]. Other countries including China and India have
good repositories of their medicinal plants and their uses [24,46,47,60]. These serve as useful sources of information for
natural products chemists interested in drug discovery (Fig. 1). Another useful approach is ethnopharmacological studies
[2,4,33,43]. This involves the use of questionnaires and or interviews to solicit information on traditional uses of plants to
treat specific diseases among the people of a given community. In some cases, identified traditional healers or practitioners
are consulted to help identify plants they use in their practice. Although this is considered a primary source of information,
the lack of trust hinders its usefulness. Traditional practitioners are sometimes reluctant to share their traditional knowledge
with researchers for fear that the researchers may “steal” their knowledge and hence, deny them their livelihood. Plants that
are frequently cited by community people or traditional practitioners are usually selected for scientific investigations. While
this might sound reasonable, frequency of use might not translate to efficacy. Instead, the high frequency could simply mean
the high availability of the plant in the community. A least cited plant can be ignored even though it might contain the most
efficacious components. It is possible that a potent plant is known only among a few people and therefore the selection of
a plant based on the frequency of use among a given community may be misleading. Given that the biological activities of

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I. Asiamah, S.A. Obiri, W. Tamekloe et al. Scientific African 20 (2023) e01593

Fig. 2. Workflow of natural product-based drug discovery approach incorporating molecular docking of known phytochemicals and reference compounds
on appropriate disease target(s); appropriate selection criteria and compound filtering is used to determine target plants for biological screening, compound
isolations and characterizations.

some plants are reported in the literature, the selection of plants for natural product drug discovery programs must consider
traditional knowledge as well as an extensive search of available literature

Phytochemicals library

Phytochemicals have demonstrated diverse biological activities including antibacterial, antiviral, anti-infective, and anti-
cancer, among many others. Natural product chemists isolate, purify, and characterize secondary metabolites for the purpose
of understanding how phytochemicals affect biological systems (Fig. 1). Pharmacologically interesting compounds serve as
leads for further optimization into new drugs. The challenge of the state-of-art equipment in most developing countries
particularly in Africa has affected our ability to undertake full natural product drug discovery programs although unique
medicinal plants abound in these countries. Research efforts have concentrated extensively on testing crude extracts and
fractions obtained by solvent partitioning on disease models either in-vitro or in-vivo (Fig. 1). In some cases where structures
of pure isolates are reported, they are usually not accompanied by biological evaluations because of insufficient quantities
to allow for biological studies. However, the reported structures present the opportunity to integrate CADD techniques into
natural products-based drug discovery programs (Fig. 2). This will involve a careful and systematic review of existing liter-
ature to determine known phytochemicals from different plants. The phytochemicals are used to create ligand libraries for
docking. Virtual screening of such libraries against appropriate drug target(s) is expected to reveal vital information about
the potential applications of plants [21,41,49,54]. Also, a search of pharmacophore models in a phytochemical library can
help identify plants likely to demonstrate efficacy against new disease conditions. Therefore, a combination of docking in-
formation with folkloric uses or ethnopharmacological findings is expected to enhance the selection of appropriate plants
for a natural products-based drug discovery program.

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Table 1
Checklist of critical questions about the protein of interest for molecular docking.

1. What class of proteins does the target protein belong to?

2. What is the known general or specific function of those classes of proteins?
3. In what organisms are those proteins expressed?
4. What are the normal biological or metabolic processes that are associated with the normal expression of the protein?
5. Is their expression implicated in disease states of any kind?
6. What is the known substrate of the protein?
7. What is their natural inhibitor and substrate?
8. Are the proteins biosynthesized in an active or inactive form?
9. What is the size range of the protein?
10. What folding conformation is often preferred by the protein?
11. What is the nature of the catalytic domain and active site of the protein?
12. What is the protein of interest’s role in disease pathogenesis?
13. Has the target protein been characterized in a host (e.g., humans)?
14. What are the implications of inhibiting or stimulating the target protein for the host?

Protein and ligand database collection

The ligand

The practical application of molecular docking relies heavily on different software and databases [29]. The widely used
software packages for docking differ in their algorithms, scoring functions, and other novel features. The potential appli-
cations and advantages of the widely used tools have been published elsewhere [6,17]. Various databases like ZINC [27],
Super Natural II [7], NPAtlas [58], NuBBEDB [50], Knap-Sack [39], CMAUP [61] and TCM@Taiwan [16] are available which
provide structural information on natural products. More recently, the launch of COCONUT, a web-based aggregated dataset
of natural products from open sources is freely available at https://coconut.naturalproducts.net. https://cocon COCONUT al-
lows researchers to browse, search, and easily download natural products [55]. The molecular structure of natural products
in their 3D form required for molecular docking is available from these databases or can be built from scratch with software
such as Spartan, and ChemDraw, among others. PubChem Database (freely available at https://pubchem.ucbi.nlm.nih.gov) has
a section that allows users to build molecules. A proper file format compatible with most docking software is the PDB file
format. Whether the structure of the isolate is downloaded from a databank or built from scratch with different software,
the file format in which the structure is downloaded or saved should be considered. In the case where the structure is saved
in a different format, Discovery Studio can be used to open the file and then converted it to the PDB file format since this
software is compatible with a lot of docking file formats.

The protein target

Drug targets are proteins or enzymes whose activities influence the survival of a disease-causing organism and therefore
inhibiting the activity of the enzyme is detrimental to the survival of the organism. Proteins critical in different disease con-
ditions have been studied and crystal or NMR structures are sometimes available in databases such as the RSCB Protein Data
Bank (PDB) (https://www.rcsb.org/), AlphaFold Protein Structure Database (https://alphafold.ebi.ac.uk/) and the SWISS-PROT
Database (https://www.uniprot.org/). The solution-based nature of NMR gives it the ability to reveal more binding sites that
is not obvious in crystal structures. The PDB repository is usually the main source of protein target structures for docking
studies with the number rapidly increasing for many years. Currently, there are over 190,0 0 0 PDB entries of protein struc-
tures. The 3D structure of the protein target can be downloaded (either in an SDF or PDB file format) from this database
for docking studies. This database contains information about specific drug target(s) including sometimes ligands (known
inhibitors, cofactors, and solvent groups) co-crystallized into them. The active site residues and critical protein-ligand in-
teractions can be gleaned from the PDB. Understanding the protein target is critical to the useful interpretation of docking
results. Thus, extensive research on the protein target of interest is required. The role of a target in a disease condition must
be clearly defined to suggest implications for its inhibition or induction. To understand the protein of interest, the following
checklist of critical questions [6,40,48,51,52] is helpful:(Table 1)
In the case of parasitic-induced conditions, there is a need to understand the life cycle of parasites and the pathophys-
iology of the disease burden they carry relative to the host (e.g., humans) [15,37]. The PDB database provides links to the
relevant literature which is a useful starting point for understanding the protein target of interest.

Molecular docking

A given medicinal plant contains different active components which account for its biological activity. When the crude
extract of a given plant demonstrates potent biological activity, compound isolations and structural characterization of the
active compound allow the use of in-silico studies to explore different potential drug targets. Docking studies usually use
already known structures in databases to explore new targets. The potential exists to use docking for natural product re-

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purposing as is done conventionally to find new uses for “old” drugs. Docking of phytochemicals from a given plant, for
example, on drug targets for emerging diseases may reveal the potential of the plant to have some form of activity against
the condition. Thus, the plant can be selected for extraction and biological testing on appropriate disease models.
In simple terms, molecular docking is a modeling technique to study how a small molecule (ligand/drug) interacts with
a macromolecule (protein/enzyme, DNA, etc.). Molecular docking basically addresses three key goals - virtual screening,
pose prediction, and binding affinity estimation [28]. The protein and ligand preparation have a prominent effect on the
docking results. Proteins and ligands are each prepared separately by automated procedures (like adding hydrogens and
charges) before docking. Most of the macromolecules and ligands come from x-ray crystallography even though NMR is
used to produce some of the structures [38]. The processes involved in producing an x-ray crystallographic structure result in
situations such as distortion of hydrogen bonds, elimination of hydrogen atoms, and atomic clashes in the crystal structure.
To perform a docking exercise, it is important to address some of the anomalies that come with the crystal structure,
addition of hydrogen facilitate saturation and stabilization of bonding interactions and binding affinity of ligand against
target [36]. Columbic interaction between partial atomic charges have been reported to dominate the binding energy and
binding structures [1,56] The ligand’s recognition by any macromolecule depends on the 3-dimensional orientation and
molecular interactions. The ligand is allowed to interact with the protein to give several poses with their binding affinities.
The results of such in-silico studies allow medicinal chemists to predict whether a given compound is likely to have useful
biological applications and is therefore worth synthesizing. In natural product studies, all known phytochemicals of one or
more herbal plants can be docked against a single or multiple protein(s) and their interactions can be visualized. There
are basically two different docking types in drug discovery: 1) precision or focus docking and 2) blind or global docking.
Docking protocols must be validated to build trust in the docking results. Here, precision, or focused docking is advised. The
ligand (native/experimental inhibitor) co-crystalized to the protein downloaded from the PDB databank is separated and
re-docked into the active site after definite moves assuming different conformational shapes. A successful docking protocol
must be able to correctly predict, to a certain tolerance limit, the native (experimental) pose and its molecular interactions.
This native interaction is compared to the docked results. If a greater number of the experimental interactions and most
especially the catalytic residues interaction are retained, then the docking protocol can be trusted to give credible results.
Once a library is generated from phytochemicals and appropriate drug target(s) is/are selected, docking is performed us-
ing free or licensed molecular docking software such as Autodock vina, PyRx, CCDC GOLD, Schrodinger, MOE, GLIDE, among
others. SwissDock and PatchDock as well are server-based docking platforms. Sometimes it is useful to compare different
platforms and select structures predicted by most or all the software. The use of multiple docking algorithms and their
scoring functions improves the likelihood of identifying active compounds. This ‘consensus-based approach’ is argued to
provide a more enriched hit list than using a single algorithm for docking and scoring [9,31]. Normally, docking of standard
reference compounds allows for a useful comparison of the types of protein-ligand interactions. Experimenter set selection
criteria are usually used to determine which binding poses or binding energies of the docked phytochemicals are carried
forward to the next stage (Fig. 2).

Drug-likeness prediction

Potent compounds with the potential to become effective drugs must be able to reach the site of action or the active site
of a biological target in the body. In addition to attaining therapeutic concentration, the molecule must stay long enough
to interact with its targets for the expected outcome to occur. This requires a drug molecule to possess a sufficient balance
between hydrophilicity and hydrophobicity. The rule-of-fives pioneered by Lipinski et al., [35] have been used successfully
in predicting the physicochemical parameters of compounds intended for oral administration. Assessment of other param-
eters such as absorption, distribution, metabolism, and excretion (ADME) is important to reduce pharmacokinetic-related
attrition at later stages of the drug development process. In-silico techniques are useful alternatives to experiments espe-
cially when physical access to compounds is limited [30]. Different in silico platforms are available freely to experts and
non-experts alike to predict drug-like and ADME properties from molecular structures. Typically, compounds that are se-
lected after docking studies are further analysed for their ADME properties and toxicity using software such as preADMET
(https://preadmet.bmdrc.kr/) and swiss ADME (http://www.swissadme.ch/) web server [18]. Other drug-like properties such
as blood–brain barrier (BBB) permeability, aqueous solubility, human intestinal absorption (HIA), human ether-a-gogo-related
gene (hERG) inhibition, rodent carcinogenicity, CYP2D6 inhibition, and CYP3A4 inhibition can also be predicted. Compounds
which enter the brain in significant quantities are likely to cause serious CNS side-effects, and therefore prediction of BBB
permeability allows filtering out of such compounds. Compounds with low aqueous solubility usually present with poor
potency while HIA is a key parameter for predicting the transportability of compounds to their targets [59]. Cardiac dys-
functions remain a major concern in drug discovery and development and therefore hERG liability must be assessed [19].
The selected compounds must be predicted for their inhibitory effect on drug-metabolizing enzymes such as CYP2D6 and
CYP3A4 to reduce potential drug-drug interactions

Implications of findings

In natural products-based drug discovery programs, docking is expected to impact various decisions. For example, phyto-
chemicals characterized from a given plant can be docked on a drug target for a new disease such as COVID-19 to determine

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whether the plant is likely to show some kind of activity in a biological study [12]. Exploring different protein targets to
determine new uses for phytochemicals in plant repurposing studies saves time and cost because plants known to contain
promising phytochemicals can be directly targeted for biological screening. Also, when the phytoconstituents of medicinal
plants traditionally used in a community for a specific disease condition are known, the plants can be repurposed for a
different disease through in-silico study. Docking results, when combined with traditional knowledge on medicinal plant is
expected to influence the plant selection decision process. Phytochemicals which demonstrate potential based on in-silico
results can be related to the plant sources to establish an agreement or otherwise with experimental results (either for the
crude or pure isolates). Additionally, in-silico findings could suggest which plants should be selected for bioactivity eval-
uation studies. Docking can help to explain the multi-target effects of natural products, simulate the effects of possible
structural modifications to optimize desirable activities and exclude undesired targets. Also, molecular docking can be com-
bined with other computer-aided drug discovery approaches such as pharmacophore modelling and molecular dynamics to
predict the activity and explore the binding mechanisms Molecular docking continues to play a pivotal role.

Concluding remarks

Drug discovery is a time-consuming and expensive process with no guarantee of success. However, the incorporation of
technological advancements in recent times is helping to reduce attrition rates, especially at the later stages of drug devel-
opment. Molecular docking continues to play a pivotal role in conventional drug discovery research as a tool to aid lead
identifications, and thus saves time and cost of novel lead discovery. Natural products remain a key source of novel chemo-
types, and the use of CADD approaches in natural products-based drug discovery efforts must be intensified. The emerging
trend of employing molecular docking as a tool to predict potential interactions between phytochemicals and disease targets
is expected to impact many decisions. Among others, by understanding the interactions between photochemical and disease
target(s), natural product chemists will be able to select potential plants for screening against new disease conditions such
as COVID-19. Although the suggestions made in this paper are not exhaustive, they provide easy-to-understand information
expected to benefit natural product scientists who are new to molecular docking and are interested in incorporating CADD
approaches in their research.

Declaration of Competing Interest

The authors declare no conflict of interest.

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