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In the chemistry literature, I often see a stated concentration (nanomolar, micromolar, millimolar) followed by qualitative judgment on the potency of the small molecule for protein inhibition. What concentration range is considered weak, and what range might a small molecule be strong enough to be lead optimized?

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The threshold for activity varies based on the target, but hit-level activity is typically 1 µM or lower. Targets are normally enzymes or receptors, so the term activity refers to an IC50 or EC50 value.

Smaller molecules have fewer potential sites for intermolecular binding than larger molecules. Therefore, small molecules rarely bind as strongly as larger compounds. For example, a hit from a typical combinatorial library may show activity (KD, IC50, Ki, EC50) at concentrations of 1 µM or lower. In contrast, a hit in a fragment library may be selected with activities of around 1 mM, which is a 1,000- fold difference in activity (a larger IC50 value implies weaker enzyme inhibitor binding).

In 1999, Teague distinguished between lead-like and drug-like hits, and combinatorial library collections. 20 Lead-like hits are characterized as having lower molecular weights (<350), activity (>0.1 µM), and clog P values (<3). The lower values give lead-like compounds room to grow into an optimized, high-affinity drug that still satisfies Lipinski’s rules. Drug-like hits have higher molecular weights (>350) and clog P values (>3) but still modest affinity (~0.1 µM). The definition of lead-like has since been used as a preliminary filter for selecting more promising hits from a screen.

The cut-off for the required activity of a hit is somewhat arbitrary. The threshold may also be based on the performance of the entire library. For example, the discovery group may count all compounds that are two or three standard deviations more active than the average of the full library.

While hits are often selected at an activity level of 1 µM (KD, IC50, etc.), structural changes may provide a lead with activity at concentrations of 0.1 µM (100 nM). Eventually, potency will typically be improved down to the 1–10 nM level during the lead optimization stage.

References:

Medicinal Chemistry E. Stevens

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  • $\begingroup$ Is this sentence and the one following supposed to say mM in it twice? "For example, a hit from a typical..." $\endgroup$ – halcyon Jul 3 '17 at 20:18
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    $\begingroup$ Well spotted!!! Thanks for this correction! Cheers :) $\endgroup$ – xavier_fakerat Jul 3 '17 at 20:39

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