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The physical chemistry profiles of successfully marketed oral drugs, backed up by substantial empirical absorption, distribution, metabolism, excretion and toxicity (AMDET) data, point to the existence of a preferred physicochemical drug-like space. The rule of five (Ro5) is a widely accepted measure of this drug-like space, but current medicinal chemistry is largely operating close to the limits of the Ro5, where ADMET risks appear to be substantially greater than at its centre. This may in part explain the high pipeline attrition experienced in the pharmaceutical industry. The lead-like concept is a viable solution to molecular inflation, since it proposes starting with low physical properties, allowing compound optimization to occur within optimal drug-like space. Fragment based drug discovery is a highly promising application of lead-like thinking. The application of ligand efficiency measures, especially lipophilicity ligand efficiency, is a means of keeping physical properties under control in lead generation and optimization programs.

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