Lead optimization

Powerful lead optimization tools for pharma and biopharma drug characterisation

In early drug discovery, the resulting leads from hit-to-lead high throughput screening (HTS) experiments undergo lead optimisation, to identify promising compounds. Potential leads are evaluated for a range of properties, including selectivity and binding mechanisms during lead optimisation, as the final step in early stage drug discovery. The purpose of lead optimisation is to maintain favourable properties in lead compounds, while improving on deficiencies in lead structure.

In order to produce a pre-clinical drug candidate, the chemical structures of lead compounds (small molecules or biologics) need to be altered to improve target specificity and selectivity. Pharmacodynamic and pharmacokinetic parameters and toxicological properties are also evaluated. Labs must acquire data on the toxicity, efficacy, stability and bioavailability of leads, in order to accurately characterise the compound and establish the route of optimisation.

Researchers in drug discovery need rapid methods to narrow down the selection of drug candidates for this downstream selectivity profiling and further investigation. High throughput DMPK (drug metabolism and pharmacokinetics) screens have become an essential part of lead optimisation, facilitating the understanding and prediction of in vivo pharmacokinetics using in vitro tests. In order to make new drugs with higher potency and safety profiles, chemical modifications to the structure of candidate drugs are made through optimisation.

Automated screening systems are becoming an important part of pharmaceutical and biopharmaceutical drug discovery labs. Mass spectrometry is used for the detection and quantitation of metabolites. MALDI Imaging is a key technique for evaluating drug candidates and their metabolites in tissue structure rapidly and accurately.

Additionally, NMR Fragment-based Screening (FBS) in the pharmaceutical industry has become a widely applied method for the discovery and optimisation of lead molecules in targeted screening campaigns.