Synthesis of C7/C8-cyclitols and C7N-aminocyclitols from maltose and X-ray crystal structure of Streptomyces coelicolor GlgEI V279S in a complex with an amylostatin GXG-like derivative

Radhika Thanvi; Thilina D Jayasinghe; Sunayana Kapil; Babatunde Samuel Obadawo; Donald R Ronning; Steven J Sucheck

doi:10.3389/fchem.2022.950433

Synthesis of C₇/C₈-cyclitols and C₇N-aminocyclitols from maltose and X-ray crystal structure of Streptomyces coelicolor GlgEI V279S in a complex with an amylostatin GXG-like derivative

Front Chem. 2022 Sep 9:10:950433. doi: 10.3389/fchem.2022.950433. eCollection 2022.

Authors

Radhika Thanvi¹, Thilina D Jayasinghe², Sunayana Kapil¹, Babatunde Samuel Obadawo¹, Donald R Ronning², Steven J Sucheck¹

Affiliations

¹ Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH, United States.
² Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, United States.

Abstract

C₇/C₈-cyclitols and C₇N-aminocyclitols find applications in the pharmaceutical sector as α-glucosidase inhibitors and in the agricultural sector as fungicides and insecticides. In this study, we identified C₇/C₈-cyclitols and C₇N-aminocyclitols as potential inhibitors of Streptomyces coelicolor (Sco) GlgEI-V279S based on the docking scores. The protein and the ligand (targets 11, 12, and 13) were prepared, the states were generated at pH 7.0 ± 2.0, and the ligands were docked into the active sites of the receptor via Glide™. The synthetic route to these targets was similar to our previously reported route used to obtain 4-⍺-glucoside of valienamine (AGV), except the protecting group for target 12 was a p-bromobenzyl (PBB) ether to preserve the alkene upon deprotection. While compounds 11-13 did not inhibit Sco GlgEI-V279S at the concentrations evaluated, an X-ray crystal structure of the Sco GlgE1-V279S/13 complex was solved to a resolution of 2.73 Å. This structure allowed assessment differences and commonality with our previously reported inhibitors and was useful for identifying enzyme-compound interactions that may be important for future inhibitor development. The Asp 394 nucleophile formed a bidentate hydrogen bond interaction with the exocyclic oxygen atoms (C(3)-OH and C(7)-OH) similar to the observed interactions with the Sco GlgEI-V279S in a complex with AGV (PDB:7MGY). In addition, the data suggest replacing the cyclohexyl group with more isosteric and hydrogen bond-donating groups to increase binding interactions in the + 1 binding site.

Keywords: C7/C8-cyclitols; C7N-aminocyclitols; Streptomyces coelicolor GlgEI; enzyme inhibitors; protein X-ray structure.