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European Biopharmaceutical Review

Bound but not Gagged

As binding kinetics continue to open the gates to greater leaps forwards in drug discovery and development, Gary Franklin at Biacore explains all

Despite significant technological advances and huge investment in approaches such as high throughput screening (HTS), the process of bringing new drugs successfully to market has not improved significantly in the past decade. Attrition rates during later development phases remain high, resulting in many costly failures and a disappointing negative trend in overall effectiveness.

Traditionally, HTS involves the rapid analysis of very large compound libraries using assays that are intrinsically prone to extremely high error rates. In many cases, the majority of ‘hits’ are false-positives and the compounds do not bind to the intended functional binding site on the target. Typically, HTS assays also depend on an equilibrium-based system within a closed in vitro environment. These assays may miss important information that is highly relevant for the in vivo therapeutic performance of the drug.

To add to the challenge, some target classes (for example, proteases), as well as particularly ‘difficult’ individual drug targets (such as those with unknown or unstable functional partners), are unsuitable for HTS assays and require an alternative approach. As a result of the difficulties outlined, numerous alternative and/or complementary approaches to HTS are being actively implemented in drug discovery and development processes.

Continuous efforts are being made to produce higher quality compound libraries and improve the quality and information content obtained during early drug discovery. This includes ‘high content’ screening (selecting compounds based on more complex biological readouts) and structural methods focused on the interaction of compounds with the target binding site (such as in silico approaches and fragment-based screening). As a result, biophysical methods – which can provide high quality, information-rich data on compound-target interactions but are generally considered as having too low throughput – are enjoying a revival in the drug discovery arena (1).

BINDING KINETICS

The majority of methods employed in drug discovery rely on steady-state measurements made at equilibrium, and have largely been regarded as providing a good reflection of the biological potency of compounds. However, drug-target interactions are dynamic processes that depend on both molecular recognition and complex stability. Binding kinetics is therefore a very important property for understanding compound-target interactions, and this is increasingly appreciated within the pharmaceutical industry. From a practical standpoint, there has been a limited range of techniques that are capable of delivering reliable kinetic data. Stop flow technologies, for example, are laborious, and their widespread use in obtaining kinetic data on compound-target interactions has been limited by a high consumption of materials.


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Gary Franklin completed his PhD in molecular biology at the University of Newcastle-upon-Tyne, before moving to Sweden in 1989. Following post-doctoral and research associate work in the fields of Gene Regulation and Cancer Biology at the Karolinska Institute, Stockholm and Uppsala University, he became Associate Professor at Uppsala University in 1997. There he held a Group Leader position at the Department of Developmental Biology & Genetics, with research focused on tumour hypoxia, funded by the Swedish Pediatric Cancer Foundation (Barncancerfonden). He joined Biacore (now part of GE Healthcare) in 2001, where he now works as Senior Marketing Communications Specialist.
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Gary Franklin
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