New paradigm for lead optimisation

Pharmaceutical researchers used to begin their evaluation of drug leads by looking at affinity and potency, but a genomics/informatics-based research culture is now growing which is starting to impinge on this classical mode, says a new Cambridge Healthtech Institute report​.

In order to make lead optimisation less time-consuming and more linear, companies are now concentrating on potential drugs leads' ADMET (absorption, distribution, metabolism, excretion and toxicological) properties and manufacturability, reports the study, entitled 'Advances in Lead Optimisation Accelerating Drug Discovery and Development.'

The study examines ways in which new technologies can contribute to early attrition of poor drug candidates, noting that this is central to the new drug discovery paradigm.

The major trend in lead optimisation is the movement toward in silico​ and high-throughput in vitro​ approaches, it says, noting that computational methods can be applied to chemical structures to predict ADMET properties even before the compound is synthesised so that only favourable compounds need to be synthesised for screening. The study also examines new approaches for predicting toxicity, and particularly the efforts of some groups to develop better animal model systems and look at ways to introduce these assays earlier in the process.

One expert interviewed for the study is Jim Blake, senior research investigator at Array Biopharma, who said: "We believe that the production of a large compound library, by itself, has limited value for drug discovery. Instead, we established chemical and structural parameters for what good leads look like, and designed our libraries so that any hits generated require less optimisation and will result in clinical candidates with a greater likelihood of success.​

The idea is that if you begin with a high-quality compound from a high-throughout (or virtual) screen, then the lead time from hit to clinic is going to be much shorter."​

A further area of growing impact, notes the report, involves the use of cells equipped with reporter gene constructs for high-throughput analysis of the expression of specific, pre-determined genes in response to compound administration.