Bridging the gap between target-based and phenotypic-based drug discovery

ABSTRACT

Introduction

The unparalleled progress in science of the last decades has brought a better understanding of the molecular mechanisms of diseases. This promoted drug discovery processes based on a target approach. However, despite the high promises associated, a critical decrease in the number of first-in-class drugs has been observed.

Areas Covered

This review analyses the challenges, advances, and opportunities associated with the main strategies of the drug discovery process, i.e. based on a rational target approach and on an empirical phenotypic approach. This review also evaluates how the gap between these two crossroads can be bridged toward a more efficient drug discovery process.

Expert opinion

The critical lack of knowledge of the complex biological networks is leading to targets not relevant for the clinical context or to drugs that present undesired adverse effects. The phenotypic systems designed by considering available molecular mechanisms can mitigate these knowledge gaps. Associated with the expansion of the chemical space and other technologies, these designs can lead to more efficient drug discoveries. Technological and scientific knowledge should also be applied to identify, as early as possible, both drug targets and mechanisms of action, leading to a more efficient drug discovery pipeline.

KEYWORDS:

• Drug discovery
• phenotypic assay
• target-based
• cellular-based assay
• systems biology

Article highlights

• The drug discovery process can be classified as a crossroad between a rational target-based approach and a more empirical phenotypic-based approach.

• The development of the omics sciences, systems biology, structure-based drug design, combinatorial chemistry and high-throughput screening systems have promoted target-based approaches over the past three decades.

• The strength of the target-based approach includes the possibility to check the target hypothesis at a molecular level. The higher limitation of this process is due to the lack of knowledge of the complex network of biological processes, that can lead to targets that are not relevant in the real disease context, or its selection did not consider adverse effects due to on- and off-target effects.

• The strength of using the phenotypic-based approach is that drug screening does not require a prior definition of the target molecule and/or the drug mechanism of action. However, this can also result in re-discoveries and discoveries that subsequently fail to modulate the disease state and/or present too high adverse effects.

• Independent of the percentage of drugs discovered by each strategy (target and phenotypic based), the number of NMEs have been significantly decreasing.

• Several developments can boost the drug discovery process, for both target- and phenotypic-based approaches, including for example: Omics sciences and system biology leading to the increase of knowledge of complex biological systems; Sophisticated cellular models more closely mimicking the heterogeneity of human diseases, like organoids derived from iPSCs; Multiplex assays, including imaging based systems, to an increase the characterization of target systems; Automation, microfluids and biochip technology, which can lead to more industrialized and efficient screening processes; Expansion of chemical libraries, and more.

• One strategy to bridge the gap between target-based and phenotypic-based processes consists of using the available knowledge of diseases and molecular mechanisms to design innovative oriented cellular-based assays for drug discovery.

• Rationally designed phenotypic assays can lead to more productive drug discovery and increase the knowledge of the system.

• After drug discovery based on rational phenotypic assays, it is advised to identify the drug target and its mechanism of action as early as possible.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One reviewer is an employee of Arena BioWorks. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This research was funded by the Fundação para a Ciência e a Tecnologia (FCT), Portugal, through grant numbers DSAIPA/DS/0117/2020 and PTDC/EQU-EQU/3708/2021.