Drug Discovery
The need for high throughput kinetics early in the drug discovery process
Generally kinetics are only investigated late in a programme by which time many compounds, slightly less potent but with a much better kinetic profile, have already been discarded. This paper argues that having kinetic information at the early stages of drug discovery can bring numerous benefits to the process.
T
he majority of drug discovery projects rely upon estimates of compound affinity to a target protein to guide lead seeking medic- inal chemistry in early stages when high compound numbers are being screened. At this stage it is now
quite common to test at IC50 level not only against the primary target but also against several selectiv- ity and toxicity targets, so choosing compounds for progression against multiple criteria. Nevertheless any efforts to measure the on and off-rates that underlie the affinity (to either the primary target or selectivity target) are left to much later stages of the campaign when fewer compounds are tested. This is simply due to the high cost and low throughput of the specialist biosensor instruments typically used to determine binding kinetics. However, evidence is plentiful that compounds with the same affinity but different on and off-rates can have a very different biological activity profile. The affinity-driven triage strategy currently used therefore results in superior compounds being rejected early in the discovery process. Improved methods and technologies enabling cost-effective, convenient and high throughput access to kinetic data would create opportunities for a much improved early drug discovery paradigm. The attributes of an ideal technology are discussed. Affinity (KD) for a target protein, derived from
IC50, is used regularly to rank compound perform- ance. KD is dependent on both the association (on) and dissociation (off) rates of the compound and it
Drug Discovery World Summer 2011
is not possible to predict these from the KD as shown in Table 1.
So, are on and off-rates critical information or merely nice to know? The overwhelming answer is that they are critical. Andersson et al1 recognise kinetic binding data as a decisive element in drug discovery, while the importance of drug-target res- idence time (as quantified by the dissociative half life of the drug-target binary complex) is empha- sised for its potential impact on duration of effect and target selectivity by Copeland et al2 and Zhang and Monsma3. Hopkins (www.hop-
kinslab.org) puts this firmly into the perspective of the patient ‘understanding the binding kinetics can help shape the clinical profile of a drug that are important to patients: efficacy, safety, duration of action, greater tolerability, indication and thera- peutic differentiation’. The following examples show why this is so.
Slow off-rates
Increased residence time gives better duration of action
A survey of the literature identifies a number of drugs, across a variety of target families, having exceptionally long duration of action, which can be ascribed to very slow off-rates when compared to other drugs of the same class. Examples include Aprepitant4, Amlodipine5, Maraviroc6, Candesartan7, Saquinavir8 and Tiotropium9. In all of these cases, affinity would have been no
39 Dr Wilma Keighley
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