Promiscuity in drug discovery on the verge of the structural revolution: recent advances and future chances

ABSTRACT

Introduction

Promiscuity denotes the ability of ligands and targets to specifically interact with multiple binding partners. Despite negative aspects like side effects, promiscuity is receiving increasing attention in drug discovery as it can enhance drug efficacy and provides a molecular basis for drug repositioning. The three-dimensional structure of ligand–target complexes delivers exclusive insights into the molecular mechanisms of promiscuity and structure-based methods enable the identification of promiscuous interactions. With the recent breakthrough in protein structure prediction, novel possibilities open up to reveal unknown connections in ligand–target interaction networks.

Areas covered

This review highlights the significance of structure in the identification and characterization of promiscuity and evaluates the potential of protein structure prediction to advance our knowledge of drug–target interaction networks. It discusses the definition and relevance of promiscuity in drug discovery and explores different approaches to detecting promiscuous ligands and targets.

Expert opinion

Examination of structural data is essential for understanding and quantifying promiscuity. The recent advancements in structure prediction have resulted in an abundance of targets that are well-suited for structure-based methods like docking. In silico approaches may eventually completely transform our understanding of drug–target networks by complementing the millions of predicted protein structures with billions of predicted drug–target interactions.

KEYWORDS:

• drug discovery
• promiscuity
• polypharmacology
• drug repositioning
• multi-target drug
• protein structure prediction
• structural bioinformatics
• structure-based

Article highlights

• Knowledge of the promiscuity of drugs and targets provides a basis for controlling and explaining side effects, increasing drug efficacy, and drug repositioning.

• Promiscuity is a common phenomenon among drugs and there are several indications that promiscuity is much more widespread than we know today.

• Structural data have revealed binding site similarity and ligand flexibility as the main drivers of ligand promiscuity, and have shown that promiscuous binding sites are typically large and hydrophobic.

• Protein structure prediction can expand the scope of structure-based screenings to investigate promiscuity, thereby uncovering the complete ligand–target interaction networks.

• Structural refinements may overcome some intrinsic limitations of current AlphaFold models.

• Investigating promiscuity with a structural approach may revolutionize drug discovery in the future.

Declaration of interest

The authors have 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 manuscript was not funded.