The Handbook of Medicinal Chemistry
Chapter 11: In Vitro Biology: Measuring Pharmacological Activity that Will Translate to Clinical Efficacy
Published:03 Feb 2023
Iain G. Dougall, Rachel L. Grimley, Per Erik Strömstedt, 2023. "In Vitro Biology: Measuring Pharmacological Activity that Will Translate to Clinical Efficacy", The Handbook of Medicinal Chemistry, Simon E Ward, Andrew Davis
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The creation of a candidate drug molecule is very complex and involves multiple cycles of different assays and tests across diverse scientific disciplines. Attrition is generally high, and currently only 10–20% of all drug discovery projects result in a novel drug. A leading cause of attrition is poor efficacy, which is often only discovered late when entering human trials. Therefore early, translatable assessment of whether the candidate molecule will modulate the target of interest in a safe and effective manner is critical. A key aspect of this assessment (which is sometimes not given the focus that is warranted) is the generation of detailed knowledge of the interaction between drug molecules and targets, and how this translates to disease modulation. In this chapter we will look at how quantitative in vitro pharmacology and mechanistic enzymology methods can be applied to characterize the action of novel compounds in terms of potency, specificity and deeper understanding of mechanisms of action, with reference to specific examples. A detailed knowledge of the drug–target interactions from the molecular to the cellular level enables better prediction of efficacy and safety and contributes to mechanistic PKPD modelling to aid dose setting and translation through to patients.