Over the past 15 years there have been extensive efforts to understand and reduce the high attrition rates of drug candidates with an increased focus on physicochemical properties. The fruits of this labor have been the generation of numerous efficiency indices, metric-based rules and visualization tools to help guide medicinal chemists in the design of new compounds with more favorable properties. This deluge of information may have had the unintended consequence of further obfuscating molecular optimizations by the inability of these scoring functions, rules and guides to reach a consensus on when a particular transformation is identified as beneficial. The difficulty in improving our chances of success may be caused by the inherent problem of properly understanding and utilizing probabilities in decision making.  Several widely used efficiency metrics such as ligand efficiency can be demonstrated as invalid despite appearing as highly plausible methods.  This presentation will discuss some possible reasons for irrational decision making in medicinal chemistry and why it is easier to improve the plausibility of success than the probability of success.

Improving the plausibility of success in drug discovery with the use of inefficient metrics

248th National Meeting (2014)

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