TY - JOUR
T1 - 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
AU - Thanvi, Radhika
AU - Jayasinghe, Thilina D.
AU - Kapil, Sunayana
AU - Obadawo, Babatunde Samuel
AU - Ronning, Donald R.
AU - Sucheck, Steven J.
N1 - Funding Information:
Initial X-ray diffraction experiments were performed at the UNMC Structural Biology Core Facility which is funded by the Fred and Pamela Bufett NCI Cancer Center Support Grant (P30CA036727). X-ray diffraction datasets were ultimately obtained using resources of the Advanced Photon Source, a U.S. department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne. National Laboratory under contract no. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economics Development Corporation and Michigan Technology Tri-Corridor (Grant 085P1000817). NIH Grant R01AI105084 to DR and SS.
Funding Information:
Initial X-ray diffraction experiments were performed at the UNMC Structural Biology Core Facility which is funded by the Fred and Pamela Bufett NCI Cancer Center Support Grant (P30CA036727). X-ray diffraction datasets were ultimately obtained using resources of the Advanced Photon Source, a U.S. department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne. National Laboratory under contract no. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economics Development Corporation and Michigan Technology Tri-Corridor (Grant 085P1000817). NIH Grant R01AI105084 to DR and SS.
Publisher Copyright:
Copyright © 2022 Thanvi, Jayasinghe, Kapil, Obadawo, Ronning and Sucheck.
PY - 2022/9/9
Y1 - 2022/9/9
N2 - 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.
AB - 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.
KW - C7/C8-cyclitols
KW - C7N-aminocyclitols
KW - Streptomyces coelicolor GlgEI
KW - enzyme inhibitors
KW - protein X-ray structure
UR - http://www.scopus.com/inward/record.url?scp=85138609208&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85138609208&partnerID=8YFLogxK
U2 - 10.3389/fchem.2022.950433
DO - 10.3389/fchem.2022.950433
M3 - Article
C2 - 36157042
AN - SCOPUS:85138609208
SN - 2296-2646
VL - 10
JO - Frontiers in Chemistry
JF - Frontiers in Chemistry
M1 - 950433
ER -