Biotransformation: Impact and Application of Metabolism in Drug Discovery

Abstract

Biotransformation has a huge impact on the efficacy and safety of drugs. Ultimately the effects of metabolism can be the lynchpin in the discovery and development cycle of a new drug. This article discusses the impact and application of biotransformation of drugs by mammalian systems, microorganisms, and recombinant enzymes, covering active and reactive metabolites, the impact of the gut microbiome on metabolism, and how insights gained from biotransformation studies can influence drug design from the combined perspectives of a CRO specializing in a range of biotransformation techniques and pharma biotransformation scientists. We include a commentary on how biology-driven approaches can complement medicinal chemistry strategies in drug optimization and the in vitro and surrogate systems available to explore and exploit biotransformation.

Effects of Microbial Transformation on the Biological Activities of Prenylated Chalcones from Angelica keiskei

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“…[148] In a general sense, the primary role of xenobiotic metabolism is to inactivate foreign substances and enhance their elimination from the body. [149] This is primarily achieved by increasing the polarity of a substance, thereby facilitating urinary excretion. Phase 1 metabolism typically results in the introduction of new a nucleophilic polar functionality (e. g., metabolic hydroxylation), or altering a current functional group to expose a nucleophilic group (e. g., metabolic dealkylation of amines and ethers, Figure 15).…”

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“…The biotransformation data guides medicinal chemists in the rational design of follow-up compounds, wherein strategic replacements (e.g., incorporation of metabolically stable substituents, introduction of polarity, increased rigidity, etc.) are introduced in lieu of the metabolically labile functional groups and the SAR for primary pharmacology and metabolic liability is reevaluated in an iterative fashion (Cerny et al, 2020;Shanu-Wilson et al, 2020).…”