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. 2013 Nov 21;5(1):2-5.
doi: 10.1021/ml4004638. eCollection 2014 Jan 9.

Improving the plausibility of success with inefficient metrics

Michael D Shultz  1
Affiliations

Improving the plausibility of success with inefficient metrics

Michael D Shultz. ACS Med Chem Lett. .

Abstract

To increase the probability of success in drug discovery, the concept of drug-like properties was introduced. Efficiency metrics that normalize potency against these properties could help reach drug-like space more efficiently. Potential reasons for the inefficient use of metrics and suboptimal decision making are discussed.

Keywords: Ligand efficiency (LE); decision making; drug-likeness; efficiency metrics; fragment-based drug design; lipophilic efficiency (LipE).

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Figures

Figure 1
Figure 1
Graphical representation of efficiency metrics for TNKS inhibitors as a function of the number of heavy atoms or clogD. (A) Plot of LE, calculated by dividing pIC50 by #HA. If m = 1.4pIC50 and x = #HA, then y = LE = m/x. (B) Plot of LE*, where #HA is subtracted from pIC50 (y = m – x). Data is colored by potency (blue > 30 μM; red = 1 nM) to highlight lack of size dependency on potency. (C) Plot of LipE†, calculated by dividing pIC50 by clogD. If m = pIC50 and x = clogD, then y = LipE†= m/x. In contrast to HAC, logD can be negative, and extremely high positive or negative values of LipE† would result as logD values approach zero. (D) Plot of LipE, where clogD is subtracted from pIC50 (y = m – x).
Figure 2
Figure 2
Distribution of 1210 oral drugs as a function of number of heavy atoms (#HA > 50 removed for clarity). Bars marking values of fragments, hits, leads, and candidates, as proposed by Mortenson and Murray, are highlighted in red.
See this image and copyright information in PMC

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