Target Selectivity and Isoform Discrimination

Many drug targets exist as families of closely related isoforms, subtypes, or isozymes — for example the subtypes of a receptor or the isoforms of an enzyme — that differ subtly in structure but often differently in physiological role. Target selectivity is a drug's preference for its intended target over related ones; isoform discrimination is the finer-grained ability to distinguish among members of the same family, which can be the difference between a clean effect and an unwanted one.

Definition

Isoform discrimination is the degree to which a drug binds and modulates one member of a closely related target family (a receptor subtype, enzyme isoform, or isozyme) in preference to the others, determined by differences in the structure of the binding site across family members.

Scope

This topic covers how drugs discriminate among receptor subtypes, enzyme isoforms, and closely related protein targets, the structural basis of that discrimination, and worked exemplars such as cyclooxygenase-2 selectivity and kinase-inhibitor selectivity. It is a reference and educational entry; it does not provide prescribing or treatment advice.

Core questions

• Why do so many drug targets exist as families of related subtypes or isoforms?
• What structural features allow a drug to tell one isoform from another?
• How is isoform selectivity measured and reported?
• What can selective and non-selective examples teach about the benefits and limits of discrimination?

Key concepts

• Receptor subtype
• Enzyme isoform / isozyme
• Binding-site complementarity
• Selectivity ratio / fold selectivity
• Cyclooxygenase-1 vs. cyclooxygenase-2 selectivity
• Kinase-inhibitor selectivity profiling
• Subtype-selective ligand

Mechanisms

Isoform discrimination arises because members of a target family, although homologous, differ in the residues lining or near their binding pocket; a drug whose shape and chemistry exploit those differences will bind one isoform with higher affinity than another. Selectivity is expressed quantitatively as a ratio of binding affinities or inhibitory potencies across isoforms. Two well-studied illustrations are the cyclooxygenase enzymes, where agents preferentially inhibiting COX-2 over COX-1 were developed to separate anti-inflammatory action from gastric effects (FitzGerald & Patrono, 2001), and protein kinases, where large-scale profiling has quantified how broadly or narrowly inhibitors distribute their activity across the kinase family (Karaman et al., 2008). Many physiologically important targets, such as G protein-coupled receptors, comprise numerous subtypes, so subtype-selective ligands are a major goal of medicinal chemistry (Sriram & Insel, 2018).

Clinical relevance

Whether a drug discriminates between isoforms is part of how its likely effect and side-effect pattern are understood — for instance the rationale behind COX-2-preferential agents. This entry describes those mechanisms for reference and evidence appraisal and is not a basis for individual treatment decisions.

Evidence & guidelines

Quantitative selectivity profiling, exemplified for kinase inhibitors by Karaman et al. (2008), and target-family surveys such as Sriram and Insel (2018) on G protein-coupled receptors provide the descriptive evidence base; standard pharmacology texts such as Rang and Dale's Pharmacology synthesise the receptor-subtype and isozyme concepts. These are descriptive and educational rather than clinical guidelines.

History

The recognition that receptors and enzymes occur as families of subtypes and isoforms unfolded through twentieth-century receptor classification and, later, molecular cloning, which revealed the genetic basis of the subtypes that classical pharmacology had inferred functionally. The cyclooxygenase story — the discovery of a second isoform, COX-2, and the deliberate design of agents preferential for it — became a landmark case study in the promise and the limits of isoform discrimination, and high-throughput selectivity profiling later made the breadth of a drug's target spectrum directly measurable.

Debates

Does isoform selectivity reliably translate into a cleaner clinical profile?

The COX-2 experience showed that selectivity for an isoform can shift, but not eliminate, a drug's harms, and that separating one effect from another at the molecular level does not guarantee a simple improvement in the whole-organism balance of benefit and risk; how far isoform selectivity should be pursued therefore remains a case-by-case judgement.

Key figures

• Garret A. FitzGerald
• Carlo Patrono

Seminal works

• karaman-2008
• fitzgerald-patrono-2001
• sriram-2018

Frequently asked questions

What is the difference between target selectivity and isoform discrimination?

Target selectivity is the broader preference of a drug for its intended target over unrelated ones, whereas isoform discrimination is the finer ability to prefer one member of a closely related target family over its near-identical relatives.

Why is selecting between isoforms hard?

Isoforms share much of their structure, so their binding sites differ only in a small number of residues; a drug must exploit those subtle differences, which is chemically demanding and often only partially achievable.