Drug Discovery & Development

Application Notes

Presentations

Lead Optimization

Optimizing leads from hit to lead discovery usually starts off with selecting the leads from secondary screening with proven specificity and the highest binding affinities to the target of interest. Often binding affinities start off in the 1 – 10 µM range, requiring potency improvements of up to five orders on magnitude before they would be considered viable drug candidates.  Along with engineering in potency and selectivity, other factors such as toxicity and bioavailability need to be considered.  The lead optimization stage will often be accompanied with structural information from ligand-target X-ray crystallization data.

Image courtesy of Ronald Sarver, Pfizer, Inc.

Data generated during secondary screening will include IC₅₀/K_i information as well as chemical structures.  This information can help in the elucidation of bioavailability and pharmacokinetics and infer structural modification.   However, very little information may be available that will give insights into how and why the hits bind to the target.  Selecting the best compounds to move into lead optimization will dramatically improve the chances of candidates with desirable potency and selectivity.  Isothermal Titration Calorimetry (ITC) fulfills a very important role by providing information on the binding forces of ligands to their target.  It is a direct readout technique and a single experiment can yield a wealth of information about binding.  This includes a quantitative measure of attractive forces such as hydrogen bonds, van der Waals interations and ionic bonds (∆H), hydrophobic interactions (∆S), and stoichiometry (n).  The information from ITC is complimentary to X-ray structural data and can be utilized help guide the medicinal chemistry process, ultimately resulting in a drug candidate that has the best potency and selectivity.