Approaching Target Selectivity by De Novo Drug Design

ABSTRACT

Introduction: The development of drug candidates with a defined selectivity profile and a unique molecular structure is of fundamental interest for drug discovery. In contrast to the costly screening of large substance libraries, the targeted de novo design of a drug by using structural information of either the biological target and/or structure–activity relationship data of active modulators offers an efficient and intellectually appealing alternative.

Areas covered: This review provides an overview on the different techniques of de novo drug design (ligand-based drug design, structure-based drug design, and fragment-based drug design) and highlights successful examples of this targeted approach toward selective modulators of therapeutically relevant targets.

Expert opinion: De novo drug design has established itself as a very efficient method for the development of potent and selective modulators for a variety of different biological target classes. The ever-growing wealth of structural data on therapeutic targets will certainly further enhance the importance of de novo design for the drug discovery process in the future. However, a consistent use of the terminology of de novo drug design in the scientific literature should be sought.

KEYWORDS:

• De novo drug design
• medicinal chemistry
• structure-based drug design
• ligand-based drug design
• fragment-based drug design
• drug discovery
• selectivity

Article Highlights

• A constant influx of novel modulators for therapeutic targets is of utmost importance to the pharmaceutical industry and academic research.

• The de novo design of drug molecules offers tremendous opportunities for drug discovery projects with respect to efficiency and structural creativity.

• De novo drug design represents a target-independent technique, which gives it a central role in the drug discovery process.

• Since structural information about therapeutic targets will continue to increase in the future, de novo drug design will also play a major role in the future.

• For both major techniques, structure-based and ligand-based approaches, successful examples are presented. Fragment-based de novo drug design is the most frequently applied technique with impressive results.

• In the scientific literature, the notion of de novo design should be used with care in order to avoid watering down this attractive field.

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.

Reviewer Disclosures

One referee is an employee of Charles River. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work is supported by grants from the Zurich University of Applied Sciences (ZHAW) for T Fischer and R Riedl and from Insubria University for S Gazzola.