The small molecule drug design cycle is comprised of multiple discreet steps including target identification, target druggability assessment, ligand identification/design, ranking of designs, ranking difficulty of synthesis, preparation, testing and data analysis. A critical step in maximizing the efficiency of the design cycle is the ability to rank order target molecules prior to synthesis. Simple docking is often not sufficient to separate out acceptable and unacceptable target molecules and designers frequently rely on additional information from various tools such as shape and electrostatic analysis, molecular dynamics simulations, and free energy perturbation (FEP) scoring. The argument can be made that absolute scoring of a concept molecule is not required and relative ranking against a known data point is sufficient to decide whether a proposal is worth investing in. In addition more difficult synthetic targets that require increased investment in synthetic resources can easily be justified when there is clear data to support the value of a proposed molecule. The use of reliable scoring methods to rank order compounds is therefore of critical interest to medicinal chemists.

Rank ordering compound designs for synthesis: When do methods work and what are some known limitations?

256th National Meeting (2018)

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