Target Based Screening

Author: Pooja Parameswaran

 

Learning Objectives

  1. Describe target-based screening
  2. Understand when target-based screening is important and provide an example
  3. List 2 applications of target-based screening

 

Summary

There are a number of approaches that can be taken to identify functions of specified molecular targets. Target-based screening is the use of recombinant technology and genomics for drug discovery. It is a high throughput method that uses defined/known molecular targets to find a drug that efficiently induces/inhibits it. It is also termed as reverse pharmacology in which scientists move in the opposite direction of the norm; instead of knowing the function and then finding the genomic component, the genomic study occurs first, and after several specific screenings, functional studies will be performed. In target-based screening, there is knowledge of the drug beforehand, so the studies and screening methods are dependent on those factors. Target-based drug discovery is dependent on a specific molecular hypothesis formulated from prior knowledge, sometimes found from phenotypic screening. (Lage, et al. 2018)
70% of successful drugs results are from target-based screening. An advantage of target-based screening is that it is simpler to execute than phenotypic approaches because the drug’s molecular mechanisms are usually known at an earlier stage. When a molecular target is known, drug discovery can utilize mutational analysis, crystallography, computational modeling, and a number of other things to understand how a drug interacts with a target. This allows efficient structure-activity relationship development, biomarker development, and future generations of that drug acting on the target. Target- based is used when the molecule ‘causing’ the disease is pre-identified and the way it works is in question. It is often used to identify a potential target for a new drug to combat an untreated disease. Validating the target is the primary objective; protein targets are most commonly used, including enzyme targets, cell-signaling receptors, and structural proteins and regulatory factors. Target validation measures the biological response it has to the drug to be clinically functional, and it is measured by the drug’s ability to induce it appropriately. (Takenaka 2008).
Fragment-based screening is a technology used in target discovery. It identifies a target protein with a library of ligands to determine which of the ligands bind strongest with the protein. NMR is also an application of target-based screening, through an automated workflow, laboratories screen for thousands of compounds to identify targets and observe binding activity. Often times in target-based screening, a gene that codes for a protein target is identified and specific compounds for high-affinity binding are found. Then, the active compounds are checked in tissues and whole organisms. (2018) Compound libraries are usually screened against an identified protein and those compounds are then optimized for potency against the pharmacokinetic properties, enzyme, and cellular activity of the protein/enzyme. However, in the scientific industry, a target is only validated when there is a drug that displays the optimal (principle) mode of action is by inhibition of the target. (Gilbert 2013).

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References

  1. Gilbert, Ian H. “Drug Discovery for Neglected Diseases: Molecular Target-Based and Phenotypic Approaches.” Journal of Medicinal Chemistry, vol. 56, no. 20, Sept. 2013, pp. 7719–7726., doi:10.1021/jm400362b.
  2. Jung, Hye Jin, and Ho Jeong Kwon. “Fig. 5 Target Based Screening of Novel Small Molecules Binding to…” ResearchGate, 1 Aug. 2018, www.researchgate.net/figure/Target-based-screening-of-novel-small-molecules-binding-to-UQCRB-New-small-molecules_fig5_235895629.
  3. Lage, Olga Maria, et al. “Current Screening Methodologies in Drug Discovery for Selected Human Diseases.” Marine Drugs, MDPI, 14 Aug. 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC6117650/.
  4. “Powerful Techniques to Develop Drug Candidates.” Bruker.com, 21 Nov. 2018, www.bruker.com/applications/pharma-biopharma/drug-discovery/lead-discovery.html.
  5. Takenaka, T. “Classical vs Reverse Pharmacology in Drug Discovery.” BJU International, vol. 88, 2008, pp. 7–10., doi:10.1111/j.1464-410x.2001.00112.x.

 

Questions

  1. Why is target-based screening important? Target-based screening is important because it allows a method for known targets to be analyzed against libraries of ligands so a drug can be produced to effectively inhibit/induce the target compound. It is a manner to work ‘backwards’ when the function/process is unknown.
  2. How is it a high-throughput method? It is a high-throughput method because a single target is screened against libraries tens of thousands of compounds to see if there is a hit/binding efficiency between the molecules. This method does numerous experiments in a short amount of time through a machine.
  3. Can you think of ways target-based screening will be used in parallel with phenotypic screening? Target-based screening can be used after phenotypic screening because the latter is usually used to find a target compound. From there, specific functional tests can be performed to identify which ligands bind and to assess the amount of hits the molecule can get.