Ligand efficiency metrics in drug discovery: the pros and cons from a practical perspective

ABSTRACT

Introduction: Ligand efficiency metrics are almost universally accepted as a valuable indicator of compound quality and an aid to reduce attrition.

Areas covered: In this review, the authors describe ligand efficiency metrics giving a balanced overview on their merits and points of weakness in order to enable the readers to gain an informed opinion. Relevant theoretical breakthroughs and drug-like properties are also illustrated. Several recent exemplary case studies are discussed in order to illustrate the main fields of application of ligand efficiency metrics.

Expert opinion: As a medicinal chemist guide, ligand efficiency metrics perform in a context- and chemotype-dependent manner; thus, they should not be used as a magic box. Since the ‘big bang’ of efficiency metrics occurred more or less ten years ago and the average time to develop a new drug is over the same period, the next few years will give a clearer outlook on the increased rate of success, if any, gained by means of these new intriguing tools.

KEYWORDS:

• Drug design
• docking
• free energy of binding
• structure activity relationships
• drug development
• fragment-based drug discovery

Article highlights

• Ligand efficiency metrics have been proposed as a valuable aid to face the dramatic reduction of the rate of success observed in drug discovery campaigns in the last few decades.

• Ligand efficiency metrics are almost universally accepted as a valuable indicator of compound quality whose benefits are mostly in the early stages of drug discovery projects.

• Ligand efficiency metrics have been successfully applied in fragment-based drug discovery (FBDD), hit to lead optimization, deconstruction exercises and may be useful to improve molecular docking.

• Regardless of questionable formal aspects, the work of the ‘founding fathers’ and their epigones has evolved the classical way of thinking about SAR and drug design.

• Room for other use is still there but with a certain level of misuse risk.

This box summarizes key points contained in the article.

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.

Additional information

Funding

This manuscript has not been funded.