Experimental and In Silico Approaches to Study Carboxylesterase Substrate Specificity
Abstract
Human carboxylesterases (CES) are enzymes that play a central role in the metabolism and biotransformation of diverse endogenous substances and xenobiotics. The two most relevant isoforms, CES1 and CES2, are crucial in clinical pharmacotherapy as they catalyze the hydrolysis of numerous approved drugs and prodrugs. Elucidating the structural basis of CES isoform substrate specificity is essential not only for understanding and anticipating the biological fate of administered drugs, but also for designing prodrugs with optimized site-specific bioactivation. Additionally, this knowledge is also important for the design of biomedically useful molecules such as subtype-targeted CES inhibitors and fluorescent probes. In this context, both experimental and computational methodologies have been used to explore the mechanistic and thermodynamic properties of CES-mediated catalysis. Experimental designs commonly employ recombinant CES or human tissue microsomes as enzyme sources, utilizing quantification methods such as spectrophotometry (UV and fluorescence) and mass spectrometry. Computational approaches fall into two categories: (1) modeling substrate: CES recognition and affinity (molecular docking, molecular dynamics simulation, and free-energy binding calculations), and (2) modeling substrate: CES reaction coordinates (hybrid QM/MM simulations). While experimental and theoretical approaches are highly synergistic in studying the catalytic properties of CES subtypes, they…
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