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Determination of absolute configuration and binding efficacy of benzimidazole-based FabI inhibitors through the support of electronic circular dichroism and MM-GBSA techniques

journal contribution
posted on 06.05.2022, 16:42 by Jinhong Ren, Tina L Mistry, Pin-Chih Su, Shahila Mehboob, Robel Demissie, Leslie Wo-Mei Fung, Arun K Ghosh, Michael JohnsonMichael Johnson
We have previously reported benzimidazole-based compounds to be potent inhibitors of FabI for Francisella tularensis (FtFabI), making them promising antimicrobial hits. Optically active enantiomers exhibit markedly differing affinities toward FtFabI. The IC50 of benzimidazole (-)-1 is ∼100× lower than the (+)-enantiomer, with similar results for the 2 enantiomers. Determining the absolute configuration for these optical compounds and elucidating their binding modes is important for further design. Electronic circular dichroism (ECD) quantum calculations have become important in determining absolute configurations of optical compounds. We determined the absolute configuration of (-)/(+)-1 and (-)/(+)-2 by comparing experimental spectra and theoretical density functional theory (DFT) simulations of ECD spectra at the B3LYP/6-311+G(2d, p) level using Gaussian09. Comparison of experimental and calculated ECD spectra indicates that the S configuration corresponds to the (-)-rotation for both compounds 1 and 2, while the R configuration corresponds to the (+)-rotation. Further, molecular dynamics simulations and MM-GBSA binding energy calculations for these two pairs of enantiomers with FtFabI show much tighter binding MM-GBSA free energies for S-1 and S-2 than for their enantiomers, R-1 and R-2, consistent with the S configuration being the more active one, and with the ECD determination of the S configuration corresponding to (-) and the R configuration corresponding to (+). Thus, our computational studies allow us to assign (-) to (S)- and (+) to (R)- for compounds 1 and 2, and to further evaluate structural changes to improve efficacy.

Funding

Novel Antibiotic Development For Biodefense | Funder: National Institutes of Health (National Institute of Allergy and Infectious Diseases) | Grant ID: U01AI077949

Development of novel dual-mode antibiotics for drug resistant S. aureus | Funder: National Institute of Allergy and Infectious Diseases | Grant ID: R41AI110090

History

Citation

Ren, J., Mistry, T. L., Su, P. -C., Mehboob, S., Demissie, R., Fung, L. W. -M., Ghosh, A. K.Johnson, M. E. (2018). Determination of absolute configuration and binding efficacy of benzimidazole-based FabI inhibitors through the support of electronic circular dichroism and MM-GBSA techniques. Bioorganic & Medicinal Chemistry Letters, 28(11), 2074-2079. https://doi.org/10.1016/j.bmcl.2018.04.052

Publisher

Elsevier BV

Language

en

issn

0960-894X