“How Were New Medicines Discovered?”, 2011-06-24 (; backlinks):
We analysed the discovery strategies and the molecular mechanisms of action (MMOAs) for new molecular entities and new biologics that were approved by the US Food and Drug Administration (FDA) in the 10-year period 1999–9200816ya.
Out of the total of 259 agents approved, 75 were first-in-class drugs with new MMOAs, and of these, 50 (67%) were small molecules and 25 (33%) were biologics.
These results 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 these two approaches, respectively—in an era in which the major focus was on target-based approaches.
There were 164 follower drugs, of which 83 (51%) were discovered with target-based approaches, 30 (18%) via phenotypic assays and 31 (19%) were biologics.
Many different biochemical mechanisms mediated the drug response at the target.
These included: reversible, irreversible and slow binding kinetics; competitive, uncompetitive and noncompetitive interactions between physiological substrates/ligands and drugs; and inhibition, activation, agonism, partial agonism, allosteric activation and induced degradation, among other mechanisms.
We conclude that an affinity-driven ‘one size fits all’ approach to drug discovery does not account for the diversity of MMOAs of approved drugs.
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.
We consider that technical risk—and, consequently, overall attrition in drug development—could be decreased for first-in-class drugs through the development and greater use of translational phenotypic assays and by considering diverse MMOAs when using a target-based, hypothesis-driven strategy.
[followup: criticized by et al 2014, vindicated by 2023] 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 1999–9200816ya.
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.
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