Current strategic trends in drug discovery: the present as prologue

ABSTRACT

Introduction

Escalating costs and inherent uncertainties associated with drug discovery invite initiatives to improve its efficiency and de-risk campaigns for inventing better therapeutics. One such initiative involves recognizing and exploiting current approaches in therapeutics invention with molecular mechanisms of action that hold promise for designing and targeting new chemical entities as drugs.

Areas covered

This perspective considers the current contextual framework around three drug-discovery approaches and evaluates their potential to help identify new targets/modalities in small-molecule molecular pharmacology: diversifying ligand-directed phenotypes for G protein-coupled receptor (GPCR) pharmacotherapeutic signaling; developing therapeutic-protein degraders and stabilizers for proximity-inducing pharmacology; and mining organelle biology for druggable therapeutic targets.

Expert opinion

The contemporary drug-discovery approaches examined appear generalizable and versatile to have applications in therapeutics invention beyond those case studies discussed herein. Accordingly, they may be considered strategic trends worthy of note in advancing the field toward novel ways of addressing pharmacotherapeutically unmet medical needs.

KEYWORDS:

• Therapeutics invention
• G protein-coupled receptor signaling bias
• allosteric drugs
• proximity-inducing modalities
• organelle targeting

Article highlights

• Productivity shortfalls and increasing operational costs exert pressures on the pharmaceutical industry to de-risk R&D and enhance translational success in bringing new and improved drugs to the clinic.

• Examination of contemporary research trends that hold promise for improving output and efficiency of discovery campaigns with new chemical entities having therapeutically advantageous molecular properties is warranted.

• As exemplified in recent research involving the µ-opioid, adenosine A₁, and cannabinoid 1 G protein-coupled receptors (GPCRs), the quest for improved GPCR modulators with pharmacological advantages over extant drugs increasingly seeks to diversify new chemical entity molecular phenotypes by incorporating properties of G-protein ligand bias and/or allostery.

• As exemplified by (pre)clinical-stage protein degraders, proximity-inducing pharmacological agents have the potential to expand the druggable proteome and generate medicines for diseases with limited, if any, extant pharmacotherapeutic options.

• As exemplified by the mitochondrion, chemical space can be productively mined and extended in the context of ‘organelle medicine’ to generate drug candidates that exert salutary effects well beyond the organelle’s prime physiological role.

• Continued computational, laboratory and clinical translational investigations involving these research trends will be necessary to establish their ultimate worth for addressing unmet medical needs through drug discovery.

This box summarizes key points contained in the article.

Declaration of interest

The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.