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Table 2 Increasing complexity of measurements for assessing new compounds in vitro

From: A perspective on multi-target drug discovery and design for complex diseases

Target Parameters Effects
Receptor (R) \(L + R\mathop{\rightleftarrows}\limits_{k_{\text{off}}}^{k_{\text{on}}}LR \to {\text{conformational change}}\) Multiple effects possible: on, off, partial, etc
Enzyme (E) Reversible \(L + E\mathop{\rightleftarrows}\limits_{k_{\text{off}}}^{k_{\text{on}}}{\text{LE}}\)
Irreversible \(L + E \mathop{\rightleftarrows}\limits_{k_{\text{off}}}^{k_{\text{on}}}{\text{LE}}\xrightarrow{{k_{\text{inact}} }}L - E\)
Decreases product, prevents depletion of substrate but can be out-competed by substrate
Inactivated enzyme; recovery depends on normal turnover of enzyme (minutes to days)
Protein or DNA (M) \(L + M\mathop{\rightleftarrows}\limits_{k_{\text{off}}}^{k_{\text{on}}}LM\) Ligand and target often at same concentration in vitro. Outcome of binding best measured downstream
Cell target (T) \(L_{\text{out}}\xrightarrow{\text{cell uptake}}\,L_{\text{in}} \xrightarrow{\text{metabolism?}}\frac{\text{Organelle uptake}}{\text{Other binding}} \to L + T\mathop{\rightleftarrows}\limits_{k_{\text{off}}}^{k_{\text{on}}}{\text{LT}}\) Concentration at target site unknown
Major effects often easy to assess (e.g., cell death) but mechanism can be obscure