Embracing Phenotypic Drug Discovery for Next-generation Therapeutics

Adhara Kaeli^*
*Correspondence: Adhara Kaeli, Department of Chemistry, University of Washington, Seattle, WA 98195, USA, Email:

Keywords

Schizophrenia • Phenotypic drug • Chemistry • Target-based drug discovery • Mechanisms • Drug development

Introduction

In the pursuit of novel therapeutics to address a myriad of diseases afflicting humanity, the pharmaceutical industry has long relied on targetbased drug discovery. This approach involves identifying a specific molecular target associated with a disease and developing compounds that interact with it. While successful in many cases, this method has limitations, often leading to high attrition rates and an inability to address complex diseases with multifaceted underlying mechanisms. In response, there has been a resurgence of interest in phenotypic drug discovery – an approach that focuses on identifying compounds based on their ability to modify the phenotype of a cell or organism, regardless of the underlying molecular target. In this article, we explore the principles, advantages and challenges of phenotypic drug discovery and its potential to revolutionize the field of therapeutics [1].

Phenotypic drug discovery involves screening large libraries of compounds for their ability to induce a desired phenotypic change in a relevant cellular or organismal model. Unlike target-based approaches, which rely on prior knowledge of the molecular mechanisms involved in a disease, phenotypic screening allows for the identification of compounds with unexpected or unknown mechanisms of action. By observing changes in cellular morphology, function, or behavior, researchers can identify compounds that modulate disease-relevant pathways or processes, providing valuable starting points for further optimization and drug development [2].

Literature Review

Advantages of phenotypic drug discovery

1. Broad spectrum of activity: Phenotypic screening can identify compounds with activity against a wide range of disease-relevant phenotypes, including those with complex or poorly understood underlying biology.

2. Novel mechanisms of action: Since phenotypic screening does not rely on knowledge of specific molecular targets, it can reveal compounds with novel mechanisms of action, potentially leading to the discovery of new drug classes.

3. Reduction of attrition rates: By focusing on the desired phenotypic outcome rather than a specific target, phenotypic drug discovery can help reduce late-stage failures in drug development, resulting in cost and time savings [3].

4. Identification of drug combinations: Phenotypic screening can also identify synergistic drug combinations that target multiple pathways or processes involved in a disease, offering new therapeutic strategies for complex diseases like cancer and infectious diseases.

Challenges and considerations: Despite its promise, phenotypic drug discovery presents several challenges.

1. Mode of action elucidation: Identifying the molecular targets and mechanisms of action of hit compounds identified through phenotypic screening can be challenging and time-consuming.

2. Off-target effects: Compounds identified through phenotypic screening may exhibit off-target effects, leading to unforeseen toxicity or lack of specificity [4,5].

3. Complexity of phenotypes: Disease phenotypes are often complex and multifactorial, making it difficult to identify relevant cellular or organismal models for screening.

4. Hit validation and optimization: Hits from phenotypic screens require rigorous validation and optimization to ensure their suitability for further development as therapeutics [6].

Discussion

Despite these challenges, the potential of phenotypic drug discovery to revolutionize the field of therapeutics is immense. Advances in high-throughput screening technologies, imaging techniques and computational biology are enabling researchers to overcome many of the obstacles associated with phenotypic screening. Furthermore, the integration of phenotypic and target-based approaches, known as phenotypic target profiling, holds promise for accelerating drug discovery and improving the success rate of drug development programs. By embracing phenotypic drug discovery as a complementary approach to target-based strategies, the pharmaceutical industry can unlock new opportunities for the development of next-generation therapeutics to address unmet medical needs.

Conclusion

Phenotypic drug discovery offers a powerful alternative to target-based approaches, allowing for the identification of compounds based on their ability to modulate disease-relevant phenotypes. While it presents challenges, advances in technology and methodology are expanding the capabilities of phenotypic screening and increasing its relevance in drug discovery. By embracing phenotypic drug discovery as part of a comprehensive drug discovery toolkit, researchers can accelerate the development of novel therapeutics and improve patient outcomes across a wide range of diseases.

Acknowledgement

None.

Conflict of Interest

None.

References

1. Astani, Akram, Jürgen Reichling and Paul Schnitzler. "Screening for antiviral activities of isolated compounds from essential oils." Evidence-Based Complement Altern Med 2011 (2011).

   Google Scholar, Crossref, Indexed at

2. Godakanda, V. Umayangana, Heyu Li, Laura Alquezar and Lixiang Zhao, et al. "Tunable drug release from blend poly (vinyl pyrrolidone)-ethyl cellulose nanofibers." Int J Pharm562 (2019): 172-179.

   Google Scholar, Crossref, Indexed at

3. Badr, Jihan M., Ghada M. Hadad, Khaled Nahriry and Hashem A. Hassanean. "Validated HPLC method for simultaneous estimation of khellol glucoside, khellin and visnagin in Ammi visnaga L. fruits and pharmaceutical preparations." Nat Prod Res 29 (2015): 593-601.

   Google Scholar, Crossref, Indexed at

4. Yan, Renhong, Yuanyuan Zhang, Yaning Li and Lu Xia, et al. "Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2." Sci 367 (2020): 1444-1448.

   Google Scholar, Crossref, Indexed at

5. Frei, Angelo. "Metal complexes, an untapped source of antibiotic potential?." Antibiotics 9 (2020): 90.

   Google Scholar, Crossref, Indexed at

6. Alexander, J. Wesley. "History of the medical use of silver." Surg Infect 10 (2009): 289-292.

   Google Scholar, Crossref, Indexed at