Probing the links between in vitro potency, ADMET and physicochemical parameters

Abstract

A common underlying assumption in current drug discovery strategies is that compounds with higher in vitro potency at their target(s) have greater potential to translate into successful, low-dose therapeutics. This has led to the development of screening cascades with in vitro potency embedded as an early filter. However, this approach is beginning to be questioned, given the bias in physicochemical properties that it can introduce early in lead generation and optimization, which is due to the often diametrically opposed relationship between physicochemical parameters associated with high in vitro potency and those associated with desirable absorption, distribution, metabolism, excretion and toxicity (ADMET) characteristics. Here, we describe analyses that probe these issues further using the ChEMBL database, which includes more than 500,000 drug discovery and marketed oral drug compounds. Key findings include: first, that oral drugs seldom possess nanomolar potency (50 nM on average); second, that many oral drugs have considerable off-target activity; and third, that in vitro potency does not correlate strongly with the therapeutic dose. These findings suggest that the perceived benefit of high in vitro potency may be negated by poorer ADMET properties.

Is there a link between selectivity and binding thermodynamics profiles?

“…However, all of these correlations were statistically non-significant on this dataset (Table 4). The general correlation between size and potency is well established [41,42], in our case the correlation between binding energy and Mw was found to be also remarkable (r= -0.45, p=0.052). Linear correlation (r) between entropy and lipophilicity (AlogP) was found to be more pronounced r=-0.63 (p=0.004).…”

The role of ligand efficiency metrics in drug discovery

“…High target potency combined with high lipophilicity may therefore also increase the risk of ADMET related attrition. 2 As a result, medicinal chemistry optimization needs to be balanced and multidimensional, 37 a difficult task that can be assisted by the use of efficiency metrics to control lipophilicity. Lipophilic ligand efficiency (LLE 7 or LipE, 43 Box 1) is a simple but important index combining in vitro potency and lipophilicity.…”

“…1,2 In studies of extensive datasets of small molecules, the fundamental properties of molecular size, lipophilicity, shape and polarity have been correlated, to varying degrees, with solubility 3 , membrane permeability 4 , metabolic stability, 5,6 receptor promiscuity, 7 in vivo toxicity, 8,9 and attrition 10,11 in drug development pipelines.…”

In pursuit of an inhibitory drug for the proton channel

“…Moreover, in vitro potency provides no strong correlate with therapeutic dose (17). The perceived benefit of high in vitro potency may be negated by poorer ADMET (absorption, distribution, metabolism, and excretion-toxicity) properties (17). Whether ClGBI or some derivate represents a good lead or not is yet to be proven, but their relatively low potency does not rule them out.…”

“…Nevertheless, despite being an important characteristic for drugs, an overemphasis on potency to drive lead optimization often results in the identification of highly potent leads with poor drug-like properties (3). Moreover, in vitro potency provides no strong correlate with therapeutic dose (17). The perceived benefit of high in vitro potency may be negated by poorer ADMET (absorption, distribution, metabolism, and excretion-toxicity) properties (17).…”