6 Drug Discovery Strategies

D
espite being a complex and interdisciplinary process, remarkable advances have been seen
in many areas of drug discovery and design. There are now several drug discovery strategies
available to drug discovery scientists in search of new, efficacious drugs.

This list highlights six strategies used to identify potential drug candidates.

1 Virtual Screening
Virtual screening (VS) makes use of in silico approaches. By harnessing computational methods, it
is possible to “virtually screen” large databases and/or chemical libraries to identify potential drug
candidates.1,2 There are several online compound databases available for VS.3

VS can be used in combination with other techniques (e.g. high-throughput screening (HTS)) or as a
standalone method. As VS relies on computer-aided molecular drug design and chemo-bioinformatics
techniques, it can be a far more cost-effective way of identifying lead candidates compared to
experimental approaches whereby you are required to “physically screen” large libraries against a
biological target.1,2 In addition, VS is a time effectual tool and labor-efficient – helping drug discovery
professionals avoid the laborious task of compound synthesis.3

There are numerous factors to consider when conducting a virtual screen. Firstly, are you virtually
screening existing compounds or taking a de novo design approach. Each comes with its advantages
and disadvantages. Existing compounds equals limited compounds, which restricts the scope of
the screen. However, follow-up studies (e.g. in vitro experiments, HTS) are easy to perform as the
compounds are readily available. If you adopt a de novo approach (whereby you virtually create new
compounds) there is no limitation on virtual compound space. However, if you do get a de novo ‘hit’
you need to determine whether the compound is synthetically available and whether it is possible to
drive its development forward.

2
High-throughput Screening
High-throughput screening (HTS) involves screening a large number of compounds in an automated
fashion against a particular biological target to identify “hits” (compounds that exert the desired effect
on the target).4,5 The success of a screen is influenced by the number and diversity of compound
library.4 Whilst HTS has successfully identified efficacious drugs (e.g. cyclosporin A and mevastatin)5 it
is usually used to identify lead compounds that can then be further optimized by medicinal chemists.
More often than not the compound that finally becomes the “finished drug product” is rather different
to the lead compound that emerged from the initial high-throughput screen.4

The success of HTS has largely been influenced by advances in liquid-handing robots, general
automation, and miniaturization. HTS assays are now capable of screening numerous different
library types, including; combinatorial chemistry, genomic, protein, and peptide over a relatively
short space of time.6,7
3 Phenotypic Screening
Phenotypic screening (PS) is used to identify molecules with the ability to alter a cell’s phenotype.
Animal models (in vivo) and cell-based assays (in vitro) can both be used to identify these molecules.8 PS
is classed as a deconvolution approach during the target identification step of discovery, because you
identify the candidate molecule’s effect before you identify the specific biological target responsible for
the phenotypic response.8,5

The greatest benefit of adopting a phenotypic approach compared to a target-based one is that you can
establish the molecule’s efficacy in the context of a cellular environment. The candidate molecule acts
on the biological target in its “normal” biological context, rather than on a purified target (which is what
you would use in a biochemical screen).9 It helps you gain a greater understanding of the complex cell
signaling networks underlying your disease of interest, in addition to reducing the likelihood of false-
positive “hits” and clinical failures by identifying factors contributing to unexpected biological activity,
and toxicities.8,5

4 Structure-based Drug Design

Advances in genomic, proteomic and bioinformatic methods has resulted in an explosion of structural
information and consequently the rapid growth of structure-based drug design (SBDD).9 The process
of SBDD starts with the cloning and purification of the target protein, allowing you to then determine
the targets structure. There are several methods suited to structure determination, including, x-ray
crystallography, nuclear magnetic resonance, and homology modeling.9

Once the structure is established, computer algorithms can be used to position or “dock” fragments
into selected “pockets” of the target structure. Numerous different programs are available for docking
fragments/compounds against a target.9 The virtual compounds are then ranked based on their steric
and electrostatic associations with the protein target at the selected position. The most promising
compounds are then further evaluated using biochemical assays. The second stage of SBDD involves
optimizing the potency of most promising compound, by reassessing the compound-target structure
and altering site on the compound. This stage can be repeated numerous times until the lead
compound is fully optimized, displaying improved specificity and binding to the target.9
5 Fragment-based Drug Design
Many of the key concepts of fragment-based drug discovery (FBDD) were outlined in the literature long
before they were physically put into practice. The theoretical basis of FBDD was published by Jenck’s in
1981 and was subsequently developed by Andrews et al. three years later.10,11 It wasn’t until 1996 that
fragment-based methods were practically applied to the field of drug discovery, by the group of Fesik
and Hajduk at Abbott laboratories.

The initial phase of FBDD involves using biophysical techniques to determine the binding of small
“fragments” to a biological target.11 A fragment-based approach allows you to identify multiple weak
affinity fragment hits for a specific target, which can then be “triaged” by medicinal chemists who can
further investigate the most promising fragments. These fragments can then be linked (non-overlapping
fragments are connected), merged (common structural parts of overlapping fragments are combined),
or grown (whereby ‘sensible chemistry’ is built around a single fragment) to produce a lead compound.

6 Ligand-based Drug Design
The ligand-based approach to drug design is usually employed to uncover the relationship between a
compound’s structure and physicochemical characteristics and its biological activity.12

Once the structure–activity relationship has been established it can be used to help predict compounds
with improved biological attributes. Ligand-based drug design (LBDD) is particularly useful when trying
to optimize a compound without prior knowledge of the target or its structure. There are numerous
LBDD approaches available including; pharmacophore models (used to find features of ligands that
control their activity), quantitative structure–activity relationships (QSAR) (used to produce quantitative
estimates of activities based on the ligand’s physiochemical properties), and similarity searching (which
explores compounds with similar properties).12

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References

1. Geromichalos, G. (2012). Virtual Screening Strategies and Application in Drug Designing. Drug

Designing: Open Access, 02(01). doi: 10.4172/2169-0138.1000e109

2. Taylor, J., & Triggle, D. (2007). Comprehensive medicinal chemistry II. Amsterdam: Elsevier. Retrieved
from: https://www.sciencedirect.com/referencework/9780080450445/comprehensive-medicinal-
chemistry-ii

3. Kar, S., & Roy, K. (2013). How far can virtual screening take us in drug discovery?. Expert Opinion on
Drug Discovery, 8(3), 245-261. doi: 10.1517/17460441.2013.761204

4. Broach, JR, Thorner, J. (1996). High-throughput screening for drug discovery. Nature. 7;384(6604
Suppl) 14-6.

5. Lansdowne, L. (2019). Target Identification & Validation in Drug Discovery. Technology Networks.
Retrieved from: https://www.technologynetworks.com/drug-discovery/articles/target-identification-
validation-in-drug-discovery-312290

6. Szymański, P., Markowicz, M., & Mikiciuk-Olasik, E. (2011). Adaptation of High-Throughput Screening
in Drug Discovery—Toxicological Screening Tests. International Journal of Molecular Sciences, 13(1),
427-452. doi: 10.3390/ijms13010427

7. Bajorath, J. (2002). Integration of virtual and high-throughput screening. Nature Reviews Drug

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8. Mason, L. (2017). The Role of Phenotypic Screening in Drug Discovery. Technology Networks.
Retrieved from: https://www.technologynetworks.com/drug-discovery/articles/the-role-of-
phenotypic-screening-in-drug-discovery-293422
9. Anderson, A. (2003). The Process of Structure-based Drug Design. Chemistry & Biology, 10(9), 787-797.
doi: 10.1016/j.chembiol.2003.09.002

10. Mason, L. (2019). Advances in Fragment-Based Drug Discovery. Technology Networks. Retrieved from:
https://www.technologynetworks.com/drug-discovery/articles/advances-in-fragment-based-drug-
discovery-303059

11. Martin Scanlon, M., & Norton, R. (2013) Fragment-based Drug Discovery, an Accessible Approach to
New Therapeutics. Technical Feature. Australian Biochemist. Retrieved from: https://www.asbmb.org.
au/oldsite/magazine/2013-December_Issue44-3/Technical%20Feature%202%20-%20Scanlon.pdf

12. Shim, J., & MacKerell, Jr., A. (2011). Computational ligand-based rational design: role of
conformational sampling and force fields in model development. Medchemcomm, 2(5), 356. doi:
10.1039/c1md00044f