Structure-based drug design:

Successes, limitations and challenges

Marina Tintelnot-Blomley

Novartis Pharma AG, Basel, Switzerland)

As with all new technologies, SBDD was initially oversold and the technical limitations were underplayed – especially after the launches of drugs discovered with structural guidance in HIV protease and neuraminidase.

Originally biased by the physiological ligand and intending to mimic its structure, structure-based work was rather ligand design than drug design. What was perceived as a success – having rational means to increase potency – could also be seen as a shortcoming. Focussing on an optimization of leads derived from a natural ligand or HTS hit, it had to carry the risk of high molecular weight and highly functionalized molecules – a bias beyond the acceptable bounds for a good pharmacokinetic profile.

This has changed due to a more balanced support of all stages within the drug discovery process. Earlier availability of structural data and very short turn-around times within the design cycle allow for a different focus. SBDD as an integral part of drug discovery, ranging from target validation to ADMET considerations, now includes the need to identify better starting points for chemistry, e.g. by fragment-based approaches and by the support of sensitive biophysical techniques.

The availability of multiple structural data also creates awareness and compensates for some of the known limitations. Ambiguities in the interpretation of x-ray data, flexibility in the binding site, different roles of water molecules, questions concerning protonation states, deficiencies in scoring functions etc. can now be partially compensated for by a wider range of structural information (including target family knowledge) and an approach driven by the human brain rather than by blind technology.

Issues such as species specificity – important for the assay systems early in the project – and specificity between related targets – essential to exclude unwanted effects – , or the development of resistance mutants are just some examples of areas gaining importance in SBDD  in a time of much easier access to structural information.