Enzymatic Late-Stage Oxidation of Lead Compounds with Solubilizing Biomimetic Docking/Protecting groups

Area of Science:

• Medicinal Chemistry
• Biocatalysis
• Drug Discovery

Background:

• Late-stage functionalization of lead compounds is crucial for generating drug metabolites and derivatives.
• Enzymatic oxidations offer high chemoselectivity but often lack predictable regioselectivity.
• Current methods for enzymatic oxidation are largely empirical, hindering targeted synthesis.

Purpose of the Study:

• To investigate the use of docking/protecting groups to steer regioselectivity in P450_BM3-mediated oxidation.
• To design novel docking/protecting groups with mild cleavage conditions and improved aqueous solubility.
• To demonstrate the utility of this approach using Vabicaserin as a tool compound.

Main Methods:

• Design and synthesis of novel docking/protecting groups.
• Biomimetic oxidation using P450_BM3.
• In silico docking and molecular dynamics studies for rationalization.
• Utilizing Vabicaserin as a model substrate.

Main Results:

• Successfully steered the regioselectivity of P450_BM3-mediated oxidation using the designed groups.
• Developed docking/protecting groups cleavable under mild conditions.
• Demonstrated improved aqueous solubility for substrates.
• In silico studies correlated with experimental outcomes.

Conclusions:

• Docking/protecting groups provide a viable strategy to control regioselectivity in enzymatic oxidations.
• This biomimetic approach enhances the efficiency of synthesizing drug derivatives and metabolites.
• The developed method offers a predictable and versatile tool for drug discovery.