Preclinical strategies that are used to identify potential drug candidates include target-based screening, phenotypic screening, modification of natural substances and biologic-based approaches. To investigate whether some strategies have been more successful than others in the discovery of new drugs, we analysed the discovery strategies and the molecular mechanism of action (MMOA) for new molecular entities and new biologics that were approved by the US Food and Drug Administration between 1999 and 2008. Out of the 259 agents that were approved, 75 were first-in-class drugs with new MMOAs, and out of these, 50 (67%) were small molecules and 25 (33%) were biologics. The results also show that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches - with 28 and 17 of these drugs coming from the two approaches, respectively - in an era in which the major focus was on target-based approaches. We postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.

The mechanism of drug action (MoA) couples molecular interactions to a physiological response. MoA includes the molecular target and the mechanism that communicates the response. The MoA defines the molecular descriptor (such as KI, kon, koff, and conformational state) for a biochemically efficient mechanism and optimal therapeutic index. Target‐focused drug discovery that is driven solely by equilibrium binding, without consideration for MoA and the molecular descriptors for an optimal therapeutic index, is a common practice in drug discovery today. In order to better understand the role of MoA in drug discovery we analyzed the MoAs of New Molecular Entities (NMEs) approved by the US FDA between 1999 and 2008. Data was collected from the product labels approved by the FDA and reports describing the discovery process. We identified that approximately 20% of the NMEs were first in class and/or had novel MoAs. Target‐focused approaches accounted for less than half of the novel MoAs and these targets were generally biologically well validated with molecular descriptors that included irreversible and slow kinetics, state dependence, induced conformations and equilibrium binding. The majority of the novel MoAs were identified from compound‐focused drug discovery by compound screening in physiological assays and modification of natural substances.