Department of Biotechnology
TOPIC TITLE:VIRTUAL SCREENING
Presented by
Student Name: K Manasa Upadhyaya
SRN: PES1201700919
PROGRAM OF STUDY: B.TECH IN BIOTECHNOLOGY
SEMESTER: 6
Under the guidance of
GUIDE NAME: Dr Prashanth Karunakar
SESSION :2
Virtual Screening
Introduction
Virtual screening/in silico screening is a computerized technique that involves screening of large
libraries of small molecules. Hits with the desired properties can be filtered faster and with less
efforts. The whole objective of this method isn’t replacement of in-vitro methods or assays, it’s
objective is to speed up the entire technique. Though discovered in the 1970’s , this technique
isn’t very popular because of its various shortcomings. Virtual screening aims to reduce the
enormous chemical space to a manageable space of a few compounds that would inhibit a target
protein for a specific disease. Virtual screening is now gaining attention in the pharmaceutical
industry because of its fast, labor saving, time saving characteristics.
Virtual Screening and drug discovery:
With the rise in the number of diseases and resistance of organisms to drugs, new techniques are
in the need of the hour. Drug discovery has a detailed list of procedures, one among them being
‘discovery of lead molecule’. Virtual screening plays an important role in determining the most
probable lead molecule. Based on the methodology employed, this can be broadly classified into
two techniques: Structure based and ligand based.
Ligand based Virtual screening:
This method chooses ligand over protein, i.e., it chooses to use the information about the active
ligands rather than the target protein for lead identification and optimization. When there is no 3d
structure of the target site, this method is obviously the best option. The two most important
aspects in this method are: an efficient similarity measure, reliable scoring function and a fast
and accurate computational screening tool. Based on the above mentioned criteria , this is further
divided into :Similarity searching, pharmacophore mapping and machine learning methods.
Similarity searching:
If an active reference structure is known, this method ranks a variety of compounds based on
similarity to the active reference. This method would obviously require a scoring function, i.e., a
measure to assess the similarity. (this makes this method a quantitative approach). The various
similarity measures that are used are molecular descriptors, similarity co-efficient and weighing
functions.
Similarity measures for virtual screening are based on the use of molecular fingerprints (binary
representations of molecule descriptors) and Tanimoto co-efficient. Molecular fingerprints depict
various different aspects of a specific molecule. This method makes string comparisons against a
biologically active known target/template. In this way, this technique identifies additional
compounds with maximum chance of displaying similar activities with the known target site.
Pharmacophore modelling:
According to the IUPAC definition, a pharmacophore model is “an ensemble of steric and
electronic features that is necessary to ensure the optimal supramolecular interactions with a
specific biological target and to trigger (or block) its biological response”. This process requires
the assembly of a set of probable active molecules/ligands by superposing. These molecules are
assumed to bind to the same molecular target with the same binding mode. Using this
information, various chemical features imperative for biological activity are assessed and a
pharmacophore model is created. This model can then be used to virtually screen libraries for
possible leads.
Structure based Virtual Screening/Protein-ligand docking:
This method starts off by obtaining the crystal structure of the target site of an enzyme of
interest. Various small molecules are then docked into the target site. The bound conformations
and free binding energies are calculated. “Single docking experiments are useful for exploring
the function of the target, and virtual screening, where a large library of compounds are docked
and ranked, may be used to identify new inhibitors for drug development”[1]
Challenges of virtual screening:
The three main challenges involved in virtual screening:
1. Limiting the enormous chemical space to limited relevant number of compounds.
2. The herculean task of assessing receptor structures: each with a thousand atoms and
many more configurations.
3. Calculation of ligand receptor binding energy.
Achievements and future prospects:
From the standpoint of exploring chemical space, computational screens of chemical databases
have identified new ligands for over 50 receptors. The ligand target structures have been
successfully computed using X-ray crystallography. Eg: Detection of druggable sites in
Asp.fumigatus (main cause of fungal diseases), discovery of high affinity of receptors to
dityrosine, etc
Even though empirical screening and high throughput screening are more preferred forms,
virtual screening is the more economical and effective method. Improving these methods gives a
better understanding of molecular interactions. Good sampling and scoring functions are being
discovered. But the challenge of the vast chemical space of thousands of compounds still
remains.
References:
[1] S. Forli, R. Huey, M. E. Pique, M. Sanner, D. S. Goodsell, and J. Arthur, “00006565-
201002000-00017,” vol. 11, no. 5, pp. 905–919, 2016, doi:
10.1038/nprot.2016.051.Computational.
[2] E. Lionta, G. Spyrou, D. K. Vassilatis, and Z. Cournia, “Structure-Based Virtual Screening
for Drug Discovery : Principles , Applications and Recent Advances,” pp. 1923–1938, 2014.
[3] G. Schneider and H. Böhm, “Virtual screening and fast automated docking methods,” vol. 7,
no. 1, pp. 64–70, 2002.
[4] D. B. Kitchen, H. Decornez, J. R. Furr, and J. Bajorath, “DOCKING AND SCORING IN
VIRTUAL SCREENING FOR DRUG DISCOVERY : METHODS AND APPLICATIONS,”
vol. 3, no. November, 2004.
[5] B. K. Shoichet, “Virtual screening of chemical libraries,” vol. 432, no. 7019, pp. 862–865,
2006.
[6] D. Des and G. D. Geromichalos, “Drug Designing : Open Access Virtual Screening
Strategies and Application in Drug Designing,” vol. 2, no. 1, pp. 1–2, 2012.
