A pharmacophore-based approach to demonstrating the scope of alcohol dehydrogenases. (1st April 2023)

• Record Type: Journal Article
• Authors: Madden, Katrina S.; Todd, Peter M.T.; Urata, Kouji; Russell, Angela J.; Vincent, Kylie A.; Reeve, Holly A.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 83(2023)
• Publication Date: 2023-04-01
• Subjects: Biocatalysis -- Medicinal chemistry -- Asymmetric synthesis -- Chiral reduction -- Pharmacophore-based screening; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2023.117255
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Barriers to the ready adoption of biocatalysis into asymmetric synthesis for early stage medicinal chemistry are addressed, using ketone reduction by alcohol dehydrogenase as a model reaction. An efficient substrate screening approach is used to show the wide substrate scope of commercial alcohol dehydrogenase enzymes, with a high tolerance to chemical groups employed in drug discovery (heterocycle, trifluoromethyl and nitrile/nitro groups) observed. We use our screening data to build a preliminary predictive pharmacophore-based screening tool using Forge software, with a precision of 0.67/1, demonstrating the potential for developing substrate screening tools for commercially available enzymes without publicly available structures. We hope that this work will facilitate a culture shift towards adopting biocatalysis alongside traditional chemical catalytic methods in early stage drug discovery.